NCBI Conserved Domain Search

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar proteins; The adaptor proteins here include homologs Grb2 in humans, Sex muscle abnormal protein 5 (Sem-5) in Caenorhabditis elegans, and Downstream of receptor kinase (drk) in Drosophila melanogaster. They are composed of one SH2 and two SH3 domains. Grb2/Sem-5/drk regulates the Ras pathway by linking the tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state. The SH2 domain of Grb2/Sem-5/drk binds class II phosphotyrosyl peptides while its SH3 domain binds to Sos and Sos-derived, proline-rich peptides. Besides it function in Ras signaling, Grb2 is also thought to play a role in apoptosis. Unlike most SH2 structures in which the peptide binds in an extended conformation (such that the +3 peptide residue occupies a hydrophobic pocket in the protein, conferring a modest degree of selectivity), Grb2 forms several hydrogen bonds via main chain atoms with the side chain of +2 Asn. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199828 Cd Length: 95 Bit Score: 170.14 E-value: 4.94e-55

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  56 KNHDWYYGRITRADAEKLLSN-KHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVKFNSLNELVEYH 134
Cdd:cd09941   1 KPHPWFHGKISRAEAEEILMNqRPDGAFLIRESESSPGDFSLSVKFGNDVQHFKVLRDGAGKYFLWVVKFNSLNELVDYH 80

                        90
                ....*....|....*
gi 23344846 135 RTASVSRSQDVKLRD 149
Cdd:cd09941  81 RTTSVSRNQQIFLRD 95

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 112.84 E-value: 4.92e-33

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11804   1 EAVAKHDFKATAEDELSFKKGSILKVLNMEDDPNWYKAELDGKEGLIPKNYI 52

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 109.25 E-value: 1.49e-31

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11805   1 RVQALYDFNPQEPGELEFRRGDIITVLDSSDPDWWKGELRGRVGIFPANYVQP 53

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

Pssm-ID: 214585 [Multi-domain] Cd Length: 84 Bit Score: 109.24 E-value: 3.39e-31

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846     58 HDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLW-VVKFNSLNELVEYHRT 136
Cdd:smart00252   1 QPWYHGFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRNEDGKFYLEgGRKFPSLVELVEHYQK 80


                   ..
gi 23344846    137 AS 138
Cdd:smart00252  81 NS 82

SH2 domain;

Pssm-ID: 425423 [Multi-domain] Cd Length: 77 Bit Score: 106.92 E-value: 1.86e-30

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846    60 WYYGRITRADAEKLLSN-KHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFL-WVVKFNSLNELVEYH 134
Cdd:pfam00017   1 WYHGKISRQEAERLLLNgKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQSTDNGGYYIsGGVKFSSLAELVEHY 77

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. Its N-terminal SH3 domain binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212879 [Multi-domain] Cd Length: 56 Bit Score: 101.26 E-value: 1.87e-28

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEMK 56
Cdd:cd11946   1 MEAIAKYDFKATADDELSFKRGDILKVLNEECDQNWYKAELNGKDGFIPKNYIEMK 56

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

Pssm-ID: 198173 [Multi-domain] Cd Length: 79 Bit Score: 92.13 E-value: 1.30e-24

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  59 DWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDG-VQHFKVLRDAQSKFFL--WVVKFNSLNELVEYH 134
Cdd:cd00173   1 PWFHGSISREEAERLLRGKPDGTFLVRESSSEPGDYVLSVRSGDGkVKHYLIERNEGGYYLLggSGRTFPSLPELVEHY 79

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212881 [Multi-domain] Cd Length: 54 Bit Score: 83.71 E-value: 1.18e-21

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11948   1 EAVALYSFQATESDELPFQKGDILKILNMEDDQNWYKAELQGREGYIPKNYIKV 54

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198189 Cd Length: 94 Bit Score: 82.82 E-value: 7.50e-21

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  58 HDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWV-VKFNSLNELVEYHRT 136
Cdd:cd09935   3 HSWYHGPISRNAAEYLLSSGINGSFLVRESESSPGQYSISLRYDGRVYHYRISEDSDGKVYVTQeHRFNTLAELVHHHSK 82


                ..
gi 23344846 137 AS 138
Cdd:cd09935  83 NA 84

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198196 Cd Length: 93 Bit Score: 81.79 E-value: 2.03e-20

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNK-HEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDaQSKFFLWVVKFNSLNELVEYHRTAS 138
Cdd:cd09943   3 WYYGRITRHQAETLLNEHgHEGDFLIRDSESNPGDYSVSLKAPGRNKHFKVQVV-DNVYCIGQRKFHTMDELVEHYKKAP 81

                        90
                ....*....|
gi 23344846 139 VSRSQDVKLR 148
Cdd:cd09943  82 IFTSEQGEKL 91

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 79.12 E-value: 7.77e-20

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846    153 EEMLVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYVT 207
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRgKEGLFPSNYVE 56

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198271 Cd Length: 97 Bit Score: 80.46 E-value: 8.91e-20

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNK-HEGAFLIRISESSPGDFSLSVKCPDGVQHFKVlrdaQSKFFLWVV---KFNSLNELVEYHR 135
Cdd:cd10408   3 WYYGKVTRHQAEMALNERgNEGDFLIRDSESSPNDFSVSLKAQGKNKHFKV----QLKECVYCIgqrKFSSMEELVEHYK 78


                ....*...
gi 23344846 136 TASVSRSQ 143
Cdd:cd10408  79 KAPIFTSE 86

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 78.73 E-value: 9.49e-20

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11949   2 VQALFDFDPQEDGELGFRRGDFIEVMDNSDPNWWKGACHGQTGMFPRNYVTP 53

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 77.89 E-value: 1.76e-19

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI-GNRKGIFPATY 205
Cdd:cd00174   2 ARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGELnGGREGLFPANY 51

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 77.39 E-value: 3.75e-19

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11782   4 AKYNFNADTGVELSFRKGDVITLTRRVDENWYEGRIGGRQGIFPVSYV 51

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 76.91 E-value: 5.59e-19

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11803   4 RALYDFEPENEGELGFKEGDIITLTNQIDENWYEGMVNGQSGFFPVNYV 52

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 76.38 E-value: 8.06e-19

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11951   2 VQAQYDFSAEDPSQLSFRRGDIIEVLDCPDPNWWRGRISGRVGFFPRNYVHP 53

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src family kinases are nonreceptor tyrosine kinases that have been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. It is thought that transforming ability of Src is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. As such blocking Src activation has been a target for drug companies. Src family members can be divided into 3 groups based on their expression pattern: 1) Src, Fyn, and Yes; 2) Blk, Fgr, Hck, Lck, and Lyn; and 3) Frk-related kinases Frk/Rak and Iyk/Bsk Of these, cellular c-Src is the best studied and most frequently implicated in oncogenesis. The c-Src contains five distinct regions: a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Src exists in both active and inactive conformations. Negative regulation occurs through phosphorylation of Tyr, resulting in an intramolecular association between phosphorylated Tyr and the SH2 domain of SRC, which locks the protein in a closed conformation. Further stabilization of the inactive state occurs through interactions between the SH3 domain and a proline-rich stretch of residues within the kinase domain. Conversely, dephosphorylation of Tyr allows SRC to assume an open conformation. Full activity requires additional autophosphorylation of a Tyr residue within the catalytic domain. Loss of the negative-regulatory C-terminal segment has been shown to result in increased activity and transforming potential. Phosphorylation of the C-terminal Tyr residue by C-terminal Src kinase (Csk) and Csk homology kinase results in increased intramolecular interactions and consequent Src inactivation. Specific phosphatases, protein tyrosine phosphatase a (PTPa) and the SH-containing phosphatases SHP1/SHP2, have also been shown to take a part in Src activation. Src is also activated by direct binding of focal adhesion kinase (Fak) and Crk-associated substrate (Cas) to the SH2 domain. SRC activity can also be regulated by numerous receptor tyrosine kinases (RTKs), such as Her2, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199827 Cd Length: 101 Bit Score: 77.24 E-value: 1.20e-18

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLL---SNKHeGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLR-DAQSKFFLWVVKFNSLNE 129
Cdd:cd09933   4 EWFFGKIKRKDAEKLLlapGNPR-GTFLIRESETTPGAYSLSVRdgddaRGDTVKHYRIRKlDNGGYYITTRATFPTLQE 82


                ....*....
gi 23344846 130 LVEYHRTAS 138
Cdd:cd09933  83 LVQHYSKDA 91

Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src non-receptor type tyrosine kinase family of proteins. The Frk subfamily is composed of Frk/Rak and Iyk/Bsk/Gst. It is expressed primarily epithelial cells. Frk is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth. Unlike the other Src members it lacks a glycine at position 2 of SH4 which is important for addition of a myristic acid moiety that is involved in targeting Src PTKs to cellular membranes. FRK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where both induce PC12 cell differentiation and beta-cell proliferation. Under conditions that cause beta-cell degeneration these proteins augment beta-cell apoptosis. The FRK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Frk has been demonstrated to interact with retinoblastoma protein. Frk regulates PTEN protein stability by phosphorylating PTEN, which in turn prevents PTEN degradation. Frk also plays a role in regulation of embryonal pancreatic beta cell formation. Frk has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its activation loop. The tryosine involved is at the same site as the tyrosine involved in the autophosphorylation of Src. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199831 Cd Length: 96 Bit Score: 77.23 E-value: 1.34e-18

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEK--LLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK-FNSLNELVEYHRT 136
Cdd:cd10369   5 WFFGAIKRADAEKqlLYSENQTGAFLIRESESQKGEFSLSVLDGGVVKHYRIRRLDEGGFFLTRRKtFSTLNEFVNYYTT 84


                ..
gi 23344846 137 AS 138
Cdd:cd10369  85 TS 86

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the C-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198217 Cd Length: 77 Bit Score: 75.15 E-value: 4.91e-18

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846  60 WYYGRITRADAEKLL-SNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVKFNSLNELVEYH 134
Cdd:cd10354   2 WFHGKISREEAYNMLvKVGGPGSFLVRESDNTPGDYSLSFRVNEGIKHFKIIPTGNNQFMMGGRYFSSLDDVIDRY 77

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198272 Cd Length: 98 Bit Score: 74.30 E-value: 2.06e-17

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLLSNKH-EGAFLIRISESSPGDFSLSVKCPDGVQHFKVlRDAQSKFFLWVVKFNSLNELVEYHRTA 137
Cdd:cd10409   2 EWYYGNVTRHQAECALNERGvEGDFLIRDSESSPSDFSVSLKAVGKNKHFKV-QLVDNVYCIGQRRFNSMDELVEHYKKA 80


                ....*.
gi 23344846 138 SVSRSQ 143
Cdd:cd10409  81 PIFTSE 86

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212767 [Multi-domain] Cd Length: 53 Bit Score: 72.53 E-value: 2.32e-17

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11833   4 ALYKFKPQENEDLEMRPGDKITLLDDSNEDWWKGKIEDRVGFFPANFV 51

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 71.69 E-value: 5.34e-17

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSD--ENWWNGEIGNRKGIFPATYV 206
Cdd:cd11842   4 ALYDFAGEQPGDLAFQKGDIITILKKSDsqNDWWTGRIGGREGIFPANYV 53

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198198 Cd Length: 98 Bit Score: 72.46 E-value: 9.35e-17

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFL--WVVKFNSLNELVEYHRTA 137
Cdd:cd09945   3 WYHGAITRIEAESLLRPCKEGSYLVRNSESTKQDYSLSLKSAKGFMHMRIQRNETGQYILgqFSRPFETIPEMIRHYCLN 82

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 70.47 E-value: 1.35e-16

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11786   3 KALYNYEGKEPGDLSFKKGDIILLRKRIDENWYHGECNGKQGFFPASYV 51

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related (Fes/Fps/Fer) proteins; The Fps family consists of members Fps/Fes and Fer/Flk/Tyk3. They are cytoplasmic protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. Fes/Fps/Fer contains three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. Members here include: Fps/Fes, Fer, Kin-31, and In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198224 Cd Length: 90 Bit Score: 70.63 E-value: 2.81e-16

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLLsnKHEGAFLIRISESSPGD---FSLSVKCPDGVQHFKVLRDAQSKFFLWVVKFNSLNEL 130
Cdd:cd10361   2 DLENEPYYHGLLPREDAEELL--KNDGDFLVRKTEPKGGGkrkLVLSVRWDGKIRHFVINRDDGGKYYIEGKSFKSISEL 79


                ....*.
gi 23344846 131 VEYHRT 136
Cdd:cd10361  80 INYYQK 85

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 69.15 E-value: 3.68e-16

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 23344846   158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE-IGNRKGIFPA 203
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKSEDGWWKGRnKGGKEGLIPS 47

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 69.21 E-value: 4.84e-16

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11964   3 VRAIYDFEAAEDNELTFKAGDIITILDDSDPNWWKGETPQGTGLFPSNFVT 53

N-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also have roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212880 [Multi-domain] Cd Length: 52 Bit Score: 68.67 E-value: 7.26e-16

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsnWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11947   1 EARGKFDFTASGEDELSFKKGDVLKILSSDDI--WFKAELNGEEGYVPKNFVDI 52

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought to play a role in PDGF-receptor signaling and regulation of apoptosis. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198255 Cd Length: 98 Bit Score: 70.10 E-value: 7.43e-16

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLW--VVKFNSLNELVEYH 134
Cdd:cd10392   3 WYHGAISRTDAENLLRLCKEASYLVRNSETSKNDFSLSLKSSQGFMHMKLSRTKEHKYVLGqnSPPFSSVPEIIHHY 79

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 68.41 E-value: 7.76e-16

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 23344846   159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESEDGWWEGINTGRTGLVPANYVE 49

Src Homology 3 domain of C-terminal Src kinase; CSK is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, CSK is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. CSK catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. It is expressed in a wide variety of tissues and plays a role, as a regulator of Src, in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. In addition, CSK also shows Src-independent functions. It is a critical component in G-protein signaling, and plays a role in cytoskeletal reorganization and cell migration. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212703 [Multi-domain] Cd Length: 57 Bit Score: 68.48 E-value: 9.38e-16

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAE-LDGKEGLIPSNYIE 54
Cdd:cd11769   2 TECIAKYNFNGASEEDLPFKKGDILTIVAVTKDPNWYKAKnKDGREGMIPANYVQ 56

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 68.14 E-value: 1.02e-15

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11823   4 ALYSYTANREDELSLQPGDIIEVHEKQDDGWWLGELNGKKGIFPATYV 51

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 68.19 E-value: 1.37e-15

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDE--NWWNGEIGNRKGIFPATYVT 207
Cdd:cd11841   2 VTALYSFEGQQPCDLSFQAGDRITVLTRTDSqfDWWEGRLRGRVGIFPANYVS 54

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198185 Cd Length: 99 Bit Score: 69.23 E-value: 1.49e-15

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846  60 WYYGRITRADAEKLLSNKHE-GAFLIRISESSPGDFSLSVKCPDG-VQHFKVLRDAQSKFFLWVVKFNSLNELVEYHR 135
Cdd:cd09931   2 WFHGHLSGKEAEKLLLEKGKpGSFLVRESQSKPGDFVLSVRTDDDkVTHIMIRCQGGKYDVGGGEEFDSLTDLVEHYK 79

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 67.71 E-value: 1.81e-15

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11772   2 FRALYDYEAQHPDELSFEEGDLLYISDKSDPNWWKATCGGKTGLIPSNYVEE 53

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 67.54 E-value: 2.05e-15

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11950   2 VRALYDFEALEDDELGFNSGDVIEVLDSSNPSWWKGRLHGKLGLFPANYVAP 53

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 67.11 E-value: 2.78e-15

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11820   3 VRALYDFEAAEDNELTFKAGEIITVLDDSDPNWWKGSNHRGEGLFPANFVT 53

N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in the carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198210 Cd Length: 81 Bit Score: 67.40 E-value: 4.14e-15

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLLSNK--HEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWV--VKFNSLNELVEYH 134
Cdd:cd10347   3 WYHGKISREVAEALLLREggRDGLFLVRESTSAPGDYVLSLLAQGEVLHYQIRRHGEDAFFSDDgpLIFHGLDTLIEHY 81

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. The SH3C of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212772 [Multi-domain] Cd Length: 52 Bit Score: 66.28 E-value: 6.26e-15

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTdRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11838   3 IALYPYESNEPGDLTFNAGDVILVT-KKDGEWWTGTIGDRTGIFPSNYVRP 52

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the Src non-receptor type tyrosine kinase family of proteins. The integration of receptor tyrosine kinase-induced RAS and Src42 signals by Connector eNhancer of KSR (CNK) as a two-component input is essential for RAF activation in Drosophila. Src42 is present in a wide variety of organisms including: California sea hare, pea aphid, yellow fever mosquito, honey bee, Panamanian leafcutter ant, and sea urchin. Src42 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198233 Cd Length: 96 Bit Score: 67.53 E-value: 6.88e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEK--LLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLW-VVKFNSLNELVEYHrt 136
Cdd:cd10370   5 WYFGKIKRIEAEKklLLPENEHGAFLIRDSESRHNDYSLSVRDGDTVKHYRIRQLDEGGFFIArRTTFRTLQELVEHY-- 82

                        90
                ....*....|....*
gi 23344846 137 asvSRSQD---VKLR 148
Cdd:cd10370  83 ---SKDSDglcVNLR 94

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 65.64 E-value: 9.76e-15

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 23344846      3 AIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAEL-DGKEGLIPSNYIE 54
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSDD-GWWKGRLgRGKEGLFPSNYVE 56

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212715 [Multi-domain] Cd Length: 53 Bit Score: 65.05 E-value: 1.60e-14

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11781   4 ALYPFKAQSAKELSLKKGDIIYIRRQIDKNWYEGEHNGRVGIFPASYV 51

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198186 Cd Length: 104 Bit Score: 66.52 E-value: 1.66e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  57 NHDWYYGRITRADAEKLLSN-KHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSkFFLWVVKFNSLNELVEYHR 135
Cdd:cd09932   3 SKEWFHANLTREQAEEMLMRvPRDGAFLVRPSETDPNSFAISFRAEGKIKHCRIKQEGRL-FVIGTSQFESLVELVSYYE 81

                        90       100
                ....*....|....*....|.
gi 23344846 136 TASVSRSqdVKLRDMIPEEML 156
Cdd:cd09932  82 KHPLYRK--IKLRYPVNEELL 100

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 65.10 E-value: 1.70e-14

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11828   1 LAEALWDHVTMDPEELGFKAGDVIEVLDMSDKDWWWGSIRDEEGWFPASFV 51

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 64.74 E-value: 2.60e-14

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11840   2 VIALFPYTAQNEDELSFQKGDIINVLSKDDPDWWRGELNGQTGLFPSNYVEP 53

C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 2 (Stac2); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac2 contains a single SH3 domain at the C-terminus unlike Stac1 and Stac3, which contain two C-terminal SH3 domains. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212918 Cd Length: 53 Bit Score: 64.58 E-value: 2.93e-14

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11985   4 ALYKFLPQENNDLPLQPGDRVMVVDDSNEDWWKGKSGDRVGFFPANFV 51

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 64.36 E-value: 3.21e-14

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11840   3 IALFPYTAQNEDELSFQKGDIINVLS-KDDPDWWRGELNGQTGLFPSNYVEP 53

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 63.77 E-value: 6.09e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTPY 209
Cdd:pfam07653   2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGRVGLVPSTAVEEI 54

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 63.88 E-value: 6.61e-14

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11963   4 VRALYDFEAVEDNELTFKHGEIIIVLDDSDANWWKGENHRGVGLFPSNFVT 54

Src homology 2 (SH2) domain found in Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (srm); Srm is a nonreceptor protein kinase that has two SH2 domains, a SH3 domain, and a kinase domain with a tyrosine residue for autophosphorylation. However it lacks an N-terminal glycine for myristoylation and a C-terminal tyrosine which suppresses kinase activity when phosphorylated. Srm is most similar to members of the Tec family who other members include: Tec, Btk/Emb, and Itk/Tsk/Emt. However Srm differs in its N-terminal unique domain it being much smaller than in the Tec family and is closer to Src. Srm is thought to be a new family of nonreceptor tyrosine kinases that may be redundant in function. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198223 Cd Length: 79 Bit Score: 64.21 E-value: 7.92e-14

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLL---SNKHeGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK-FNSLNELVEYH 134
Cdd:cd10360   2 WYFSGISRTQAQQLLlspPNEP-GAFLIRPSESSLGGYSLSVRAQAKVCHYRICMAPSGSLYLQKGRlFPGLEELLAYY 79

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 62.69 E-value: 1.36e-13

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11996   2 QVIAMYDYTANNEDELSFSKGQLINVLN-KDDPDWWQGEINGVTGLFPSNYVKM 54

N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [IVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198203 Cd Length: 99 Bit Score: 63.96 E-value: 1.69e-13

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSNKHE-GAFLIRISESSPGDFSLSVKCPDGVQHFKVlRDAQSKFFLWV-VKFNSLNELVEYH 134
Cdd:cd10340   2 WFHPVISGIEAENLLKTRGVdGSFLARPSKSNPGDFTLSVRRGDEVTHIKI-QNTGDYYDLYGgEKFATLSELVQYY 77

Src homology 2 domain found in SH2 domain-containing adapter proteins D (SHD); The expression of SHD is restricted to the brain. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198253 Cd Length: 98 Bit Score: 63.56 E-value: 2.49e-13

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK--FNSLNELVEYH 134
Cdd:cd10390   3 WFHGPLSRADAENLLSLCKEGSYLVRLSETRPQDCSLSLRSSQGFLHLKFARTRENQVVLGQHSgpFPSVPELVLHY 79

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins are a family of phorbol ester- and diacylglycerol-responsive GTPase-activating proteins. Alpha1-chimerin (formerly known as n-chimerin) and alpha2-chimerin are alternatively spliced products of a single gene, as are beta1- and beta2-chimerin. alpha1- and beta1-chimerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas alpha2- and beta2-chimerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors. All of the isoforms contain a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. Other C1 domain-containing diacylglycerol receptors including: PKC, Munc-13 proteins, phorbol ester binding scaffolding proteins involved in Ca2+-stimulated exocytosis, and RasGRPs, diacylglycerol-activated guanine-nucleotide exchange factors (GEFs) for Ras and Rap1. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198215 Cd Length: 91 Bit Score: 63.15 E-value: 2.58e-13

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 23344846  61 YYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK-FNSLNELV 131
Cdd:cd10352   9 YHGLISREEAEQLLSGASDGSYLIRESSRDDGYYTLSLRFNGKVKNYKLYYDGKNHYHYVGEKrFDTIHDLV 80

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, Vav2 and Vav3 are more ubiquitously expressed. The members here include insect and amphibian Vavs. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198193 Cd Length: 102 Bit Score: 63.08 E-value: 3.05e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  58 HDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK-FNSLNELVEYHRT 136
Cdd:cd09940   5 FLWFVGEMERDTAENRLENRPDGTYLVRVRPQGETQYALSIKYNGDVKHMKIEQRSDGLYYLSESRhFKSLVELVNYYER 84


                ....*.
gi 23344846 137 ASVSRS 142
Cdd:cd09940  85 NSLGEN 90

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110alpha, and 3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198184 Cd Length: 104 Bit Score: 63.20 E-value: 3.10e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISeSSPGDFSLSVKCPDGVQHFKVLRDAQSkfFLWVVKFN---SLNELVEYHRT 136
Cdd:cd09930   8 WLVGDINRTQAEELLRGKPDGTFLIRES-STQGCYACSVVCNGEVKHCVIYKTETG--YGFAEPYNlyeSLKELVLHYAH 84


                ....*...
gi 23344846 137 ASVSRSQD 144
Cdd:cd09930  85 NSLEQHND 92

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are members of the CSK-family of protein tyrosine kinases. These proteins suppress activity of Src-family kinases (SFK) by selectively phosphorylating the conserved C-terminal tail regulatory tyrosine by a similar mechanism. CHK is also capable of inhibiting SFKs by a non-catalytic mechanism that involves binding of CHK to SFKs to form stable protein complexes. The unphosphorylated form of SFKs is inhibited by CSK and CHK by a two-step mechanism. The first step involves the formation of a complex of SFKs with CSK/CHK with the SFKs in the complex are inactive. The second step, involves the phosphorylation of the C-terminal tail tyrosine of SFKs, which then dissociates and adopt an inactive conformation. The structural basis of how the phosphorylated SFKs dissociate from CSK/CHK to adopt the inactive conformation is not known. The inactive conformation of SFKs is stabilized by two intramolecular inhibitory interactions: (a) the pYT:SH2 interaction in which the phosphorylated C-terminal tail tyrosine (YT) binds to the SH2 domain, and (b) the linker:SH3 interaction of which the SH2-kinase domain linker binds to the SH3 domain. SFKs are activated by multiple mechanisms including binding of the ligands to the SH2 and SH3 domains to displace the two inhibitory intramolecular interactions, autophosphorylation, and dephosphorylation of YT. By selective phosphorylation and the non-catalytic inhibitory mechanism CSK and CHK are able to inhibit the active forms of SFKs. CSK and CHK are regulated by phosphorylation and inter-domain interactions. They both contain SH3, SH2, and kinase domains separated by the SH3-SH2 connector and SH2 kinase linker, intervening segments separating the three domains. They lack a conserved tyrosine phosphorylation site in the kinase domain and the C-terminal tail regulatory tyrosine phosphorylation site. The CSK SH2 domain is crucial for stabilizing the kinase domain in the active conformation. A disulfide bond here regulates CSK kinase activity. The subcellular localization and activity of CSK are regulated by its SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198190 Cd Length: 98 Bit Score: 63.08 E-value: 3.10e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLR-------DAQSKFFlwvvkfnSLNELVE 132
Cdd:cd09937   5 WFHGKISREEAERLLQPPEDGLFLVRESTNYPGDYTLCVSFEGKVEHYRVIYrngkltiDEEEYFE-------NLIQLVE 77


                ...
gi 23344846 133 YHR 135
Cdd:cd09937  78 HYT 80

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. It is expressed in the brain, T-cells, and NK cells. The unique domain of Lck mediates its interaction with two T-cell surface molecules, CD4 and CD8. It associates with their cytoplasmic tails on CD4 T helper cells and CD8 cytotoxic T cells to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck phosphorylase the intracellular chains of the CD3 and zeta-chains of the TCR complex, allowing ZAP-70 to bind them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates Linker of Activated T cells (LAT), a transmembrane protein that serves as a docking site for proteins including: Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). The tyrosine phosphorylation cascade culminates in the intracellular mobilization of a calcium ions and activation of important signaling cascades within the lymphocyte, including the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-kappaB, and AP-1. These transcription factors regulate the production cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains a SH3 domain, a SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198225 Cd Length: 101 Bit Score: 62.96 E-value: 3.27e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLS---NKHeGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWV-VKFNSLNEL 130
Cdd:cd10362   5 WFFKNLSRNDAERQLLapgNTH-GSFLIRESETTAGSFSLSVRdfdqnQGEVVKHYKIRNLDNGGFYISPrITFPGLHEL 83


                ....*...
gi 23344846 131 VEYHRTAS 138
Cdd:cd10362  84 VRHYTNAS 91

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198188 Cd Length: 104 Bit Score: 62.80 E-value: 4.07e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  58 HDWYYGRITRADAEKLLSNK-HEGAFLIRISeSSPGDFSLSV--KCPDG--VQHFKVLRDAQSKFFLwVVK--FNSLNEL 130
Cdd:cd09934   6 YEWYVGDMSRQRAESLLKQEdKEGCFVVRNS-STKGLYTVSLftKVPGSphVKHYHIKQNARSEFYL-AEKhcFETIPEL 83


                ....*
gi 23344846 131 VEYHR 135
Cdd:cd09934  84 INYHQ 88

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 61.32 E-value: 4.45e-13

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAEL-DGKEGLIPSNY 52
Cdd:cd00174   2 ARALYDYEAQDDDELSFKKGDIITVLEKDDD-GWWEGELnGGREGLFPANY 51

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212809 [Multi-domain] Cd Length: 58 Bit Score: 60.99 E-value: 6.90e-13

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRS-----DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11876   4 ALFDYDARGEDELTLRRGQPVEVLSKDaavsgDEGWWTGKIGDKVGIFPSNYVAP 58

Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast tumor kinase (Brk); Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumors. PTK6 (9). PTK6 contains a SH3 domain, a SH2 domain, and catalytic domains. For the case of the non-receptor protein-tyrosine kinases, the SH2 domain is typically involved in negative regulation of kinase activity by binding to a phosphorylated tyrosine residue near to the C terminus. The C-terminal sequence of PTK6 (PTSpYENPT where pY is phosphotyrosine) is thought to be a self-ligand for the SH2 domain. The structure of the SH2 domain resembles other SH2 domains except for a centrally located four-stranded antiparallel beta-sheet (strands betaA, betaB, betaC, and betaD). There are also differences in the loop length which might be responsible for PTK6 ligand specificity. There are two possible means of regulation of PTK6: autoinhibitory with the phosphorylation of Tyr playing a role in its negative regulation and autophosphorylation at this site, though it has been shown that PTK6 might phosphorylate signal transduction-associated proteins Sam68 and signal transducing adaptor family member 2 (STAP/BKS) in vivo. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198221 Cd Length: 100 Bit Score: 62.07 E-value: 9.92e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLS--NKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFL-WVVKFNSLNELVEYHRT 136
Cdd:cd10358   4 WFFGCISRSEAVRRLQaeGNATGAFLIRVSEKPSADYVLSVRDTQAVRHYKIWRRAGGRLHLnEAVSFLSLPELVNYHRA 83


                ....
gi 23344846 137 ASVS 140
Cdd:cd10358  84 QSLS 87

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 60.29 E-value: 1.11e-12

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 23344846     4 IAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELD-GKEGLIPS 50
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKSED-GWWKGRNKgGKEGLIPS 47

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src non-receptor type tyrosine kinase family of proteins. Src is thought to play a role in the regulation of embryonic development and cell growth. Members here include v-Src and c-Src. v-Src lacks the C-terminal inhibitory phosphorylation site and is therefore constitutively active as opposed to normal cellular src (c-Src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-Src is an oncogene whereas c-Src is a proto-oncogene. c-Src consists of three domains, an N-terminal SH3 domain, a central SH2 domain and a tyrosine kinase domain. The SH2 and SH3 domains work together in the auto-inhibition of the kinase domain. The phosphorylation of an inhibitory tyrosine near the c-terminus of the protein produces a binding site for the SH2 domain which then facilitates binding of the SH3 domain to a polyproline site within the linker between the SH2 domain and the kinase domain. Binding of the SH3 domain inactivates the enzyme. This allows for multiple mechanisms for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, or competitive binding of a polyproline binding site to the SH3 domain. Unlike most other Src members Src lacks cysteine residues in the SH4 domain that undergo palmitylation. Serine and threonine phosphorylation sites have also been identified in the unique domains of Src and are believed to modulate protein-protein interactions or regulate catalytic activity. Alternatively spliced forms of Src, which contain 6- or 11-amino acid insertions in the SH3 domain, are expressed in CNS neurons. c-Src has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198228 Cd Length: 101 Bit Score: 61.60 E-value: 1.35e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLLSN--KHEGAFLIRISESSPGDFSLSVKCPDG-----VQHFKVLRDAQSKFFLWV-VKFNSLNEL 130
Cdd:cd10365   4 EWYFGKITRRESERLLLNaeNPRGTFLVRESETTKGAYCLSVSDFDNakglnVKHYKIRKLDSGGFYITSrTQFNSLQQL 83


                ....*
gi 23344846 131 VEYHR 135
Cdd:cd10365  84 VAYYS 88

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, Fgr; Fgr is a member of the Src non-receptor type tyrosine kinase family of proteins. The protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. Fgr is expressed in B-cells and myeloid cells, localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified Fgr has been shown to interact with Wiskott-Aldrich syndrome protein. Fgr has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198230 Cd Length: 101 Bit Score: 61.46 E-value: 1.45e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLL--SNKHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWV-VKFNSLNEL 130
Cdd:cd10367   4 EWYFGKIGRKDAERQLlsPGNPRGAFLIRESETTKGAYSLSIRdwdqnRGDHVKHYKIRKLDTGGYYITTrAQFDTVQEL 83


                ....
gi 23344846 131 VEYH 134
Cdd:cd10367  84 VQHY 87

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212991 [Multi-domain] Cd Length: 58 Bit Score: 60.34 E-value: 1.48e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRS-----DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12058   1 LWTALYDYEASGEDELSLRRGDVVEVLSQDaavsgDDGWWAGKIRHRLGIFPANYVTR 58

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198200 [Multi-domain] Cd Length: 136 Bit Score: 62.35 E-value: 1.56e-12

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 23344846  54 EMKNHDWYYGRITRADAEKLLSNkhEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQS 115
Cdd:cd10337   2 DLRSHAWYHGRIPRQVAESLVQR--EGDFLVRDSLSSPGDYVLTCRWKGQPLHFKINRVVLR 61

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 60.02 E-value: 1.66e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDEnWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11992   4 ALYPYSSSEPGDLTFNEGEEILVTQKDGE-WWTGSIEDRTGIFPSNYVRP 52

Src homology 2 domain found in the SH2 domain containing protein 4A (SH2D4A); SH2D4A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198213 Cd Length: 103 Bit Score: 61.10 E-value: 2.37e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  50 SNYIEmknhDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGdFSLSVKCPDGVQHFKVLRDAQSKFFLWV--VKFNSL 127
Cdd:cd10350   3 SDTIA----PWFHGILTLKKANELLLSTMPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASADSYSFLGVdqLQHATL 77

                        90
                ....*....|...
gi 23344846 128 NELVEYHRTASVS 140
Cdd:cd10350  78 ADLVEYHKEEPIT 90

Src homology 2 domain found in hematopoietic SH2 (HSH2) protein; HSH2 is thought to function as an adapter protein involved in tyrosine kinase signaling. It may also be involved in regulating cytokine signaling and cytoskeletal reorganization in hematopoietic cells. HSH2 contains several putative protein-binding motifs, SH3-binding proline-rich regions, and phosphotyrosine sites, but lacks enzymatic motifs. HSH2 was found to interact with cytokine-regulated tyrosine kinase c-FES and an activated Cdc42-associated tyrosine kinase ACK1. HSH2 binds c-FES through both its C-terminal region and its N-terminal region including the SH2 domain and binds ACK1 via its N-terminal proline-rich region. Both kinases bound and tyrosine-phosphorylated HSH2 in mammalian cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198199 Cd Length: 102 Bit Score: 60.67 E-value: 2.84e-12

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  59 DWYYGRITRADAEKLLSNKHEGAFLIRISESSPGdFSLSVKCPDGVQHF--KVLRDAQSKFFLWVVKFNSLNELVEYHR 135
Cdd:cd09946   8 EWFHGAISREAAENMLESQPLGSFLIRVSHSHVG-YTLSYKAQSSCRHFmvKLLDDGTFMIPGEKVAHTSLHALVTFHQ 85

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide variety of pathways including regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. An adapter protein, SHC has been implicated in Ras activation following the stimulation of a number of different receptors, including growth factors [insulin, epidermal growth factor (EGF), nerve growth factor, and platelet derived growth factor (PDGF)], cytokines [interleukins 2, 3, and 5], erythropoietin, and granulocyte/macrophage colony-stimulating factor, and antigens [T-cell and B-cell receptors]. SHC has been shown to bind to tyrosine-phosphorylated receptors, and receptor stimulation leads to tyrosine phosphorylation of SHC. Upon phosphorylation, SHC interacts with another adapter protein, Grb2, which binds to the Ras GTP/GDP exchange factor mSOS which leads to Ras activation. SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198179 Cd Length: 104 Bit Score: 60.44 E-value: 3.16e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNkhEGAFLIRISESSPGDFSLSvkcpdGVQ-----HFkVLRDAQSKFFLWVVKFNSLNELVEYH 134
Cdd:cd09925   9 WYHGKMSRRDAESLLQT--DGDFLVRESTTTPGQYVLT-----GMQngqpkHL-LLVDPEGVVRTKDRVFESISHLINYH 80


                ....*
gi 23344846 135 RTASV 139
Cdd:cd09925  81 VTNGL 85

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 58.85 E-value: 3.64e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMeDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11772   4 ALYDYEAQHPDELSFEEGDLLYISDK-SDPNWWKATCGGKTGLIPSNYVE 52

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 59.06 E-value: 3.79e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYV 206
Cdd:cd11812   2 VVALYDYTANRSDELTIHRGDIIRVLYKDNDNWWFGSLVNgQQGYFPANYV 52

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 58.84 E-value: 4.62e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTdRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11991   4 AMYTYESNEQGDLTFQQGDVILVT-KKDGDWWTGTVGDKTGVFPSNYVRP 52

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 58.43 E-value: 6.34e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEdDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11995   2 QVIGMYDYTAQNDDELAFSKGQIINVLNKE-DPDWWKGELNGQVGLFPSNYVKL 54

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 58.10 E-value: 6.74e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI---GNRKGIFPATY 205
Cdd:cd11821   2 VRALYDCQADNDDELTFSEGEIIVVTGEEDDEWWEGHIegdPSRRGVFPVSF 53

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 58.10 E-value: 6.91e-12

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11826   2 VVALYDYTADKDDELSFQEGDIIYVTKKNDDGWYEGVLNGVTGLFPGNYVE 52

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198218 Cd Length: 92 Bit Score: 59.41 E-value: 7.44e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEK-LLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAqSKFFLWVVKFNSLNELVE 132
Cdd:cd10355   2 LLQSLGWYHGNLTRHAAEAlLLSNGVDGSYLLRNSNEGTGLFSLSVRAKDSVKHFHVEYTG-YSFKFGFNEFSSLQDFVK 80


                .
gi 23344846 133 Y 133
Cdd:cd10355  81 H 81

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212751 [Multi-domain] Cd Length: 50 Bit Score: 58.26 E-value: 7.53e-12

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATY 205
Cdd:cd11817   2 AVALYDFTGETEEDLSFQRGDRILVTEHLDAEWSRGRLNGREGIFPRAF 50

Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198214 Cd Length: 103 Bit Score: 59.52 E-value: 8.39e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGdFSLSVKCPDGVQHFkvLRDAQSKF--FLWV--VKFNSLNELVEYHR 135
Cdd:cd10351   9 WFHGIISREEAEALLMNATEGSFLVRVSEKIWG-YTLSYRLQSGFKHF--LVDASGDFysFLGVdpNRHATLTDLIDFHK 85


                ....*..
gi 23344846 136 TASVSRS 142
Cdd:cd10351  86 EEIITTS 92

Src homology 2 domain found in SH2 domain-containing adapter protein E (SHE); SHE is expressed in heart, lung, brain, and skeletal muscle. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198254 Cd Length: 98 Bit Score: 59.20 E-value: 9.13e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK--FNSLNELVEYHRTA 137
Cdd:cd10391   3 WYHGSISRAEAESRLQPCKEASYLVRNSESGNSKYSIALKTSQGCVHIIVAQTKDNKYTLNQTSavFDSIPEVVHYYSNE 82

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 57.71 E-value: 1.01e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11877   1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKTGWFPSNYVKE 53

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform a type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198281 Cd Length: 101 Bit Score: 58.86 E-value: 1.41e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEK-LLSNKH-EGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLR-DAQSKFFLWVVKFNSLNEL 130
Cdd:cd10418   4 EWYFGKLGRKDAERqLLSFGNpRGTFLIRESETTKGAYSLSIRdwddmKGDHVKHYKIRKlDNGGYYITTRAQFETLQQL 83


                ....
gi 23344846 131 VEYH 134
Cdd:cd10418  84 VQHY 87

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 3 (Stac3); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212919 [Multi-domain] Cd Length: 53 Bit Score: 56.84 E-value: 2.35e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11986   4 ALYRFKALEKDDLDFHPGERITVIDDSNEEWWRGKIGEKTGYFPMNFI 51

First Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212861 Cd Length: 54 Bit Score: 56.85 E-value: 2.39e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11928   4 KALYSYEGKEPGDLKFNKGDIIILRRKVDENWYHGELNGCHGFLPASYI 52

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 56.61 E-value: 2.73e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11824   3 SVLYDYTAQEDDELSISKGDVVAVIEKGEDGWWTVERNGQKGLVPGTYLE 52

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 56.65 E-value: 2.74e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11827   2 CKALYAYDAQDTDELSFNEGDIIEILKEDPSGWWTGRLRGKEGLFPGNYVE 52

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of adapter proteins that negatively regulate cellular signaling initiated by tyrosine kinases. It has a myristylated N-terminus, SH3 and SH2 domains with high homology to Src family tyrosine kinases, and a unique C-terminal tail, which is important for c-Cbl binding. SLAP negatively regulates platelet-derived growth factor (PDGF)-induced mitogenesis in fibroblasts and regulates F-actin assembly for dorsal ruffles formation. c-Cbl mediated SLAP inhibition towards actin remodeling. Moreover, SLAP enhanced PDGF-induced c-Cbl phosphorylation by SFK. In contrast, SLAP mitogenic inhibition was not mediated by c-Cbl, but it rather involved a competitive mechanism with SFK for PDGF-receptor (PDGFR) association and mitogenic signaling. Accordingly, phosphorylation of the Src mitogenic substrates Stat3 and Shc were reduced by SLAP. Thus, we concluded that SLAP regulates PDGFR signaling by two independent mechanisms: a competitive mechanism for PDGF-induced Src mitogenic signaling and a non-competitive mechanism for dorsal ruffles formation mediated by c-Cbl. SLAP is a hematopoietic adaptor containing Src homology (SH)3 and SH2 motifs and a unique carboxy terminus. Unlike c-Src, SLAP lacks a tyrosine kinase domain. Unlike c-Src, SLAP does not impact resorptive function of mature osteoclasts but induces their early apoptosis. SLAP negatively regulates differentiation of osteoclasts and proliferation of their precursors. Conversely, SLAP decreases osteoclast death by inhibiting activation of caspase 3. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198207 Cd Length: 104 Bit Score: 57.89 E-value: 2.92e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  49 PSNYIEMKNHDWYYGRITRADAEKLLS--NKHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWV 121
Cdd:cd10344   1 PSNYVAKVYHGWLFEGLSREKAEELLMlpGNQVGSFLIRESETRRGCYSLSVRhrgsqSRDSVKHYRIFRLDNGWFYISP 80

                        90
                ....*....|....
gi 23344846 122 -VKFNSLNELVEYH 134
Cdd:cd10344  81 rLTFQCLEDMVNHY 94

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 56.57 E-value: 3.09e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRS---DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11884   2 VVAVRAYITRDQTLLSFHKGDVIKLLPKEgplDPGWLFGTLDGRSGAFPKEYVQP 56

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198178 Cd Length: 81 Bit Score: 57.21 E-value: 3.11e-11

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRdAQSKFFLW-----VVKFNSLNELVEY 133
Cdd:cd09923   2 WYWGGITRYEAEELLAGKPEGTFLVRDSSDSRYLFSVSFRTYGRTLHARIEY-SNGRFSFDssdpsVPRFPCVVELIEH 79

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 56.53 E-value: 3.13e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11996   3 VIAMYDYTANNEDELSFSKGQLINVLNKDDPDWWQGEINGVTGLFPSNYV 52

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 56.70 E-value: 3.14e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12142   3 RVLFDYNPVAPDELALKKGDVIEVISKEteDEGWWEGELNGRRGFFPDNFVMP 55

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198251 Cd Length: 101 Bit Score: 57.75 E-value: 3.22e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDaQSKFFLW-----VVKFNSLN 128
Cdd:cd10388   6 ELKDCGWYWGPMSWEDAEKVLSNKPDGSFLVRDSSDDRYIFSLSFRSQGSVHHTRIEQY-QGTFSLGsrnkfVDRSQSLV 84


                ....
gi 23344846 129 ELVE 132
Cdd:cd10388  85 EFIE 88

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 56.51 E-value: 3.34e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12054   4 KVLFEYVPQNEDELELKVGDIIDINEEVEEGWWSGTLNGKSGLFPSNFV 52

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 56.38 E-value: 3.58e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11961   2 AKALYDYDAAEDNELSFFENDKIINIEFVDDDWWLGECHGSRGLFPSNYV 51

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 56.18 E-value: 3.71e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVT-DRSDENWWNGEIGNRK-GIFPATYVTP 208
Cdd:cd11763   1 KVRALYDFDSQPSGELSLRAGEVLTITrQDVGDGWLEGRNSRGEvGLFPSSYVEI 55

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 56.25 E-value: 3.98e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRS----DENWWNGEIGNRKGIFPATYV 206
Cdd:cd11762   1 LVRALYDYEAQSDEELSFPEGAIIRILRKDdngvDDGWWEGEFNGRVGVFPSLVV 55

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198180 [Multi-domain] Cd Length: 106 Bit Score: 57.48 E-value: 4.19e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWVVKFNSLNELVEYH 134
Cdd:cd09926   9 WYFGPMSRQEAQELLQGQRHGVFLVRDSSTIPGDYVLSVSensrvSHYIINSLGQPAPNQSRYRIGDQEFDDLPALLEFY 88


                .
gi 23344846 135 R 135
Cdd:cd09926  89 K 89

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212853 [Multi-domain] Cd Length: 55 Bit Score: 56.17 E-value: 4.38e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11920   4 RAVYDFKAQTSKELSFKKGDTVYILRKIDQNWYEGEHHGRVGIFPISYV 52

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 55.89 E-value: 4.94e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVIT-VTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11843   2 VRALYDYEGQESDELSFKAGDILTkLEEEDEQGWCKGRLDGRVGLYPANYV 52

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 55.78 E-value: 5.16e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI-GNRKGIFPATYVT 207
Cdd:cd11819   4 ALYDYQAAEDNEISFVEGDIITQIEQIDEGWWLGVNaKGQKGLFPANYVE 53

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 55.82 E-value: 6.14e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11875   2 ARVLFDYEAENEDELTLREGDIVTILSKDceDKGWWKGELNGKRGVFPDNFVEP 55

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 55.62 E-value: 7.40e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11956   6 ACFDYTGRTAQELSFKRGDVLLLHSKASSDWWRGEHNGMRGLIPHKYIS 54

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 55.54 E-value: 7.68e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRS-----DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12059   4 AVFDYEASAEDELTLRRGDRVEVLSKDsavsgDEGWWTGKINDRVGIFPSNYVTS 58

First Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212862 Cd Length: 54 Bit Score: 55.33 E-value: 8.21e-11

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11929   4 KALCNYRGHNPGDLKFNKGDVILLRRQLDENWYLGEINGVSGIFPASSV 52

Src homology 3 domain of Slit-Robo GTPase Activating Proteins; Slit-Robo GTPase Activating Proteins (srGAPs) are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. Vertebrates contain three isoforms of srGAPs (srGAP1-3), all of which are expressed during embryonic and early development in the nervous system but with different localization and timing. A fourth member has also been reported (srGAP4, also called ARHGAP4). srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212743 [Multi-domain] Cd Length: 53 Bit Score: 55.10 E-value: 9.04e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKiLNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11809   1 EATAQFDYTGRSERELSFKKGDSLT-LYRQVSDDWWRGQLNGQDGLVPHKYI 51

Second Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the second SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212721 [Multi-domain] Cd Length: 53 Bit Score: 55.03 E-value: 9.67e-11

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELD---FRRGDVITVTDRSDENWWNGEIGNRKGIFPATY 205
Cdd:cd11787   4 ALYDFEMKDEDEKDcltFKKGDVITVIRRVDENWAEGRLGDKIGIFPISF 53

N-terminal Src Homology 3 domain of Ct10 Regulator of Kinase adaptor proteins; CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers. The N-terminal SH3 domain of CRK binds a number of target proteins including DOCK180, C3G, SOS, and cABL. The CRK family includes two alternatively spliced protein forms, CRKI and CRKII, that are expressed by the CRK gene, and the CRK-like (CRKL) protein, which is expressed by a distinct gene (CRKL). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212692 [Multi-domain] Cd Length: 55 Bit Score: 55.06 E-value: 1.11e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGnRKGIFPATYVT 207
Cdd:cd11758   3 VRALFDFPGNDDEDLPFKKGEILTVIRKPEEQWWNARnsEG-KTGMIPVPYVE 54

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 54.96 E-value: 1.16e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11995   3 VIGMYDYTAQNDDELAFSKGQIINVLNKEDPDWWKGELNGQVGLFPSNYV 52

Src homology 3 domain of RUN and SH3 domain-containing proteins 1 and 2; RUSC1 and RUSC2, that were originally characterized in silico. They are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC2, also called Iporin, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212744 Cd Length: 50 Bit Score: 54.76 E-value: 1.27e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATY 205
Cdd:cd11810   2 VRALCHHVATDSGQLSFRKGDILRVIARVDDDWLLCTRGSTKGLVPLSY 50

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. There are 3 members of the Grb7 family of proteins: Grb7, Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR). Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198197 [Multi-domain] Cd Length: 108 Bit Score: 56.28 E-value: 1.37e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKH--EGAFLIRISESSPGDFSLSVKCPDGVQHFKVL---RDAQSKFFL--WVVKFNSLNELVE 132
Cdd:cd09944   7 WFHGGISRDEAARLIRQQGlvDGVFLVRESQSNPGAFVLSLKHGQKIKHYQIIpieDEGQWYFTLddGVTKFYDLLQLVE 86


                ...
gi 23344846 133 YHR 135
Cdd:cd09944  87 FYQ 89

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and SLAM-associated protein (SAP); The SH2-containing inositol-5'-phosphatase, SHIP (also called SHIP1/SHIP1a), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, SHIP dampens down PIP3 mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. PIP3 recruits lipid-binding pleckstrin homology(PH) domain-containing proteins to the inner wall of the plasma membrane and activates them. PH domain-containing downstream effectors include the survival/proliferation enhancing serine/threonine kinase, Akt (protein kinase B), the tyrosine kinase, Btk, the regulator of protein translation, S6K, and the Rac and cdc42 guanine nucleotide exchange factor, Vav. SHIP is believed to act as a tumor suppressor during leukemogenesis and lymphomagenesis, and may play a role in activating the immune system to combat cancer. SHIP contains an N-terminal SH2 domain, a centrally located phosphatase domain that specifically hydrolyzes the 5'-phosphate from PIP3, PI-4,5-P2 and inositol-1,3,4,5- tetrakisphosphate (IP4), a C2 domain, that is an allosteric activating site when bound by SHIP's enzymatic product, PI-3,4-P2; 2 NPXY motifs that bind proteins with a phosphotyrosine binding (Shc, Dok 1, Dok 2) or an SH2 (p85a, SHIP2) domain; and a proline-rich domain consisting of four PxxP motifs that bind a subset of SH3-containing proteins including Grb2, Src, Lyn, Hck, Abl, PLCg1, and PIAS1. The SH2 domain of SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule, Cas, c-Cbl, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs). The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX(V/I), which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198206 Cd Length: 103 Bit Score: 56.30 E-value: 1.41e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNK-HEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLW------VVKFNSLNELVE 132
Cdd:cd10343   5 WYHGNITRSKAEELLSKAgKDGSFLVRDSESVSGAYALCVLYQNCVHTYRILPNAEDKLSVQasegvpVRFFTTLPELIE 84


                ...
gi 23344846 133 YHR 135
Cdd:cd10343  85 FYQ 87

First Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212860 Cd Length: 54 Bit Score: 54.96 E-value: 1.41e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11927   4 KALYNYEGKEPGDLKFSKGDIIILRRQVDENWYHGEVNGIHGFFPTNFV 52

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212702 [Multi-domain] Cd Length: 54 Bit Score: 54.59 E-value: 1.58e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWW-----NGEIgnrkGIFPATYVTP 208
Cdd:cd11768   1 IVVALYDFQPIEPGDLPLEKGEEYVVLDDSNEHWWrardkNGNE----GYIPSNYVTE 54

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 54.51 E-value: 1.80e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAEL--DGKEGLIPSNY 52
Cdd:cd11845   3 VALYDYEARTDDDLSFKKGDRLQILD-DSDGDWWLARHlsTGKEGYIPSNY 52

N-terminal Src Homology 3 domain of Ct10 Regulator of Kinase adaptor proteins; CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers. The N-terminal SH3 domain of CRK binds a number of target proteins including DOCK180, C3G, SOS, and cABL. The CRK family includes two alternatively spliced protein forms, CRKI and CRKII, that are expressed by the CRK gene, and the CRK-like (CRKL) protein, which is expressed by a distinct gene (CRKL). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212692 [Multi-domain] Cd Length: 55 Bit Score: 54.29 E-value: 2.18e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAE-LDGKEGLIPSNYIE 54
Cdd:cd11758   4 RALFDFPGNDDEDLPFKKGEILTVIR-KPEEQWWNARnSEGKTGMIPVPYVE 54

Third N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212730 Cd Length: 51 Bit Score: 54.28 E-value: 2.29e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11796   4 VLQDLSAQLDEELDLREGDVVTITGILDKGWFRGELNGRRGIFPEGFV 51

Src homology 2 (SH2) domain found in the Vav1 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav1 plays a role in T-cell and B-cell development and activation. It has been identified as the specific binding partner of Nef proteins from HIV-1, resulting in morphological changes, cytoskeletal rearrangements, and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Vav1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and EZH2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198268 Cd Length: 103 Bit Score: 55.79 E-value: 2.32e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  58 HDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLrdaqSKFFLWVVK----FNSLNELVEY 133
Cdd:cd10405   5 HLWYAGPMERAGAESILANRSDGTYLVRQRVKDAAEFAISIKYNVEVKHIKIM----TAEGLYRITekkaFRGLTELVEF 80


                ....*.
gi 23344846 134 HRTASV 139
Cdd:cd10405  81 YQQNSL 86

Src homology 2 domain found in SH2 domain-containing adapter protein B (SHB); SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198252 Cd Length: 97 Bit Score: 55.48 E-value: 2.42e-10

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKvLRDAQSKFFLW--VVKFNSLNELVEYHRT 136
Cdd:cd10389   3 WYHGAISRGDAENLLRLCKECSYLVRNSQTSKHDYSLSLKSNQGFMHMK-LAKTKEKYVLGqnSPPFDSVPEVIHYYTT 80

C-terminal Src Homology 3 domain of the p67phox subunit of NADPH oxidase and similar proteins; This subfamily is composed of p67phox, NADPH oxidase activator 1 (Noxa1), and similar proteins. p67phox, also called Neutrophil cytosol factor 2 (NCF-2), and Noxa1 are homologs and are the cytosolic subunits of the phagocytic (Nox2) and nonphagocytic (Nox1) NADPH oxidase complexes, respectively. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox and Noxa1 play regulatory roles. p67phox contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. Noxa1 has a similar domain architecture except it is lacking the N-terminal SH3 domain. The TPR domain of both binds activated GTP-bound Rac, while the C-terminal SH3 domain of p67phox and Noxa1 binds the polyproline motif found at the C-terminus of p47phox and Noxo1, respectively. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212803 [Multi-domain] Cd Length: 53 Bit Score: 54.07 E-value: 2.73e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11870   2 VVALHRYEAQGPEDLGFREGDTIDVLSEVNEAWLEGHSDGRVGIFPKCFVVP 53

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the brain and is required for neurite outgrowth. It may also play a role in the protection and migration of embryonic stem cells. Treatment-related acute myeloid leukemia (AML) has been reported resulting from mixed-lineage leukemia (MLL)-GAS7 translocations as a complication of primary cancer treatment. GAS7 contains an N-terminal SH3 domain, followed by a WW domain, and a central F-BAR domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212763 [Multi-domain] Cd Length: 52 Bit Score: 54.06 E-value: 2.84e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 156 LVQALYDFVPQESGE-LDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11829   1 LCRTLYAFTGEQHQQgLSFEAGELIRVLQAPDGGWWEGEKDGLRGWFPASYV 52

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 53.79 E-value: 3.10e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11830   2 AKARYDFCARDMRELSLKEGDVVKIYNKKGQQGWWRGEINGRIGWFPSTYVE 53

Src homology 2 (SH2) domain found in the Vav2 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav2 is a GEF for RhoA, RhoB and RhoG and may activate Rac1 and Cdc42. Vav2 has been shown to interact with CD19 and Grb2. Alternatively spliced transcript variants encoding different isoforms have been found for Vav2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198269 Cd Length: 103 Bit Score: 55.07 E-value: 3.70e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVKFNSLNELVEYHRTASV 139
Cdd:cd10406   7 WFAGNMERQQTDNLLKSHASGTYLIRERPAEAERFAISIKFNDEVKHIKVVEKDNWIHITEAKKFESLLELVEYYQCHSL 86


                ...
gi 23344846 140 SRS 142
Cdd:cd10406  87 KES 89

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 53.58 E-value: 3.97e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11843   4 ALYDYEGQESDELSFKAGDILTKLEEEDEQGWCKGRLDGRVGLYPANYVE 53

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212907 Cd Length: 54 Bit Score: 53.53 E-value: 4.62e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11974   4 EALWDHVTMDDQELAFKAGDVIRVLEASNKDWWWGRNEDREAWFPASFV 52

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in hemopoietic cells. HCK is proposed to couple the Fc receptor to the activation of the respiratory burst. It may also play a role in neutrophil migration and in the degranulation of neutrophils. It has two different translational starts that have different subcellular localization. HCK has been shown to interact with BCR gene, ELMO1 Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. HCK has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198226 Cd Length: 104 Bit Score: 54.59 E-value: 6.59e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEK--LLSNKHEGAFLIRISESSPGDFSLSVKCPDG-----VQHFKVLRDAQSKFFLWV-VKFNSLNEL 130
Cdd:cd10363   4 EWFFKGISRKDAERqlLAPGNMLGSFMIRDSETTKGSYSLSVRDYDPqhgdtVKHYKIRTLDNGGFYISPrSTFSTLQEL 83


                ....*...
gi 23344846 131 VEYHRTAS 138
Cdd:cd10363  84 VDHYKKGN 91

Src homology 2 domain found in the SH2 domain containing protein 7 (SH2D7); SH2D7 contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199832 Cd Length: 102 Bit Score: 54.13 E-value: 6.97e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGdFSLSVKCPDGVQHFkVLRDAQSKFFLW---VVKFNSLNELVEYHRT 136
Cdd:cd10417   9 WFHGFITRKQTEQLLRDKALGSFLIRLSDRATG-YILSYRGSDRCRHF-VINQLRNRRYLIsgdTSSHSTLAELVRHYQE 86


                ...
gi 23344846 137 ASV 139
Cdd:cd10417  87 VQL 89

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 53.05 E-value: 7.07e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGI-----FPATY 205
Cdd:cd11883   2 VVALYDFTPKSKNQLSFKAGDIIYVLNKDPSGWWDGVIISSSGKvkrgwFPSNY 55

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 52.74 E-value: 7.17e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846   8 DFSATADDELSFRKTQILKILNME-DDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11875   7 DYEAENEDELTLREGDIVTILSKDcEDKGWWKGELNGKRGVFPDNFVE 54

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 52.64 E-value: 7.56e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11856   4 AIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVRKGDKEGWVPASYLEP 53

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 52.63 E-value: 8.73e-10

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDR-SDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11830   4 ARYDFCARDMRELSLKEGDVVKIYNKkGQQGWWRGEINGRIGWFPSTYV 52

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 52.50 E-value: 8.89e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12046   1 QVVALFSYEASQPEDLEFQKGDVILVLSKVNEDWLEGQCKGKIGIFPSAFVED 53

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212849 [Multi-domain] Cd Length: 59 Bit Score: 52.69 E-value: 9.93e-10

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRK--GIFPATYVTP 208
Cdd:cd11916   5 QALYSYAPQNDDELELRDGDIVDVMEKCDDGWFVGTSRRTKqfGTFPGNYVKL 57

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 52.53 E-value: 1.08e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILkILNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11956   2 VEAVACFDYTGRTAQELSFKRGDVL-LLHSKASSDWWRGEHNGMRGLIPHKYI 53

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 52.35 E-value: 1.12e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11782   1 EARAKYNFNADTGVELSFRKGDVITLTRRVDE-NWYEGRIGGRQGIFPVSYVQ 52

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198195 Cd Length: 110 Bit Score: 53.87 E-value: 1.32e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRdAQSKF-FLWVVKFNSLNELVE 132
Cdd:cd09942   3 SLQEAEWYWGDISREEVNEKMRDTPDGTFLVRDASTMKGDYTLTLRKGGNNKLIKIFH-RDGKYgFSDPLTFNSVVELIN 81

                        90
                ....*....|....*...
gi 23344846 133 YHRTASVS---RSQDVKL 147
Cdd:cd09942  82 YYRNNSLAeynRKLDVKL 99

Third Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. The third SH3 domain of Sla1p can bind ubiquitin while retaining the ability to bind proline-rich ligands; monoubiquitination of target proteins signals internalization and sorting through the endocytic pathway. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212709 [Multi-domain] Cd Length: 57 Bit Score: 52.32 E-value: 1.35e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD--GKEGLIPSNYIE 54
Cdd:cd11775   2 RGKVLYDFDAQSDDELTVKEGDVVYILDDKKSKDWWMVENVstGKEGVVPASYIE 56

First Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212852 [Multi-domain] Cd Length: 55 Bit Score: 52.27 E-value: 1.45e-09

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11919   4 RAKFDFKAQTLKELPLQKGDIVYIYKQIDQNWYEGEHHGRVGIFPRSYI 52

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 52.14 E-value: 1.47e-09

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12073   5 ALYDYQGEGDDEISFDPQETITDIEMVDEGWWKGTCHGHRGLFPANYV 52

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in the hematopoietic cells, in neural tissues, liver, and adipose tissue. There are two alternatively spliced forms of Lyn. Lyn plays an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation, triggering a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phospholipase C2 (PLC2) and phosphatidyl inositol-3 kinase. These kinases play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FC RIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1 which further down modulate signaling pathways, attenuate cell activation and can mediate tolerance. Lyn also plays a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1) leading to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. It is the primary Src family member involved in signaling downstream of the B cell receptor. Lyn plays an unusual, 2-fold role in B cell receptor signaling; it is essential for initiation of signaling but is also later involved in negative regulation of the signal. Lyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198227 Cd Length: 101 Bit Score: 53.06 E-value: 1.68e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLL---SNKhEGAFLIRISESSPGDFSLSVKCPDG-----VQHFKVLRDAQSKFFLWV-VKFNSLNE 129
Cdd:cd10364   4 EWFFKDITRKDAERQLlapGNS-AGAFLIRESETLKGSYSLSVRDYDPqhgdvIKHYKIRSLDNGGYYISPrITFPCISD 82


                ....*....
gi 23344846 130 LVEYHRTAS 138
Cdd:cd10364  83 MIKHYQKQS 91

Src homology 2 (SH2) domain found in SH2 domain-bearing protein kinases A and C (ShkA and ShkC); SH2-bearing genes cloned from Dictyostelium include two transcription factors, STATa and STATc, and a signaling factor, SHK1 (shkA). A database search of the Dictyostelium discoideum genome revealed two additional putative STAT sequences, dd-STATb and dd-STATd, and four additional putative SHK genes, dd-SHK2 (shkB), dd-SHK3 (shkC), dd-SHK4 (shkD), and dd-SHK5 (shkE). This model contains members of shkA and shkC. All of the SHK members are most closely related to the protein kinases found in plants. However these kinases in plants are not conjugated to any SH2 or SH2-like sequences. Alignment data indicates that the SHK SH2 domains carry some features of the STAT SH2 domains in Dictyostelium. When STATc's linker domain was used for a BLAST search, the sequence between the protein kinase domain and the SH2 domain (the linker) of SHK was recovered, suggesting a close relationship among these molecules within this region. SHK's linker domain is predicted to contain an alpha-helix which is indeed homologous to that of STAT. Based on the phylogenetic alignment, SH2 domains can be grouped into two categories, STAT-type and Src-type. SHK family members are in between, but are closer to the STAT-type which indicates a close relationship between SHK and STAT families in their SH2 domains and further supports the notion that SHKs linker-SH2 domain evolved from STAT or STATL (STAT-like Linker-SH2) domain found in plants. In SHK, STAT, and SPT6, the linker-SH2 domains all reside exclusively in the C-terminal regions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198219 Cd Length: 113 Bit Score: 53.38 E-value: 1.76e-09

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLS-VKCPDGVQHFKVLRdAQSKFFLWVVKFNSLNELV 131
Cdd:cd10356  12 WFHGDISTSESENRLNGKPEGTFLVRFSTSEPGAYTISkVSKNGGISHQRIHR-PGGKFQVNNSKYLSVKELI 83

Src Homology 3 domain of eumetazoan Peroxisomal biogenesis factor 13; PEX13 is a peroxin and is required for protein import into the peroxisomal matrix and membrane. It is an integral membrane protein that is essential for the localization of PEX14 and the import of proteins containing the peroxisome matrix targeting signals, PTS1 and PTS2. Mutations of the PEX13 gene in humans lead to a wide range of peroxisome biogenesis disorders (PBDs), the most severe of which is known as Zellweger syndrome (ZS), a severe multisystem disorder characterized by hypotonia, psychomotor retardation, and neuronal migration defects. PEX13 contains two transmembrane regions and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212798 Cd Length: 58 Bit Score: 51.86 E-value: 1.79e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSN---WYRAELDGKE-GLIPSNYIE 54
Cdd:cd11864   1 VARAEYDFVAESEDELSFRAGDKLRLAPKELQPRvrgWLLATVDGQKiGLVPANYVK 57

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 51.65 E-value: 1.84e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11827   4 ALYAYDAQDTDELSFNEGDIIEILK-EDPSGWWTGRLRGKEGLFPGNYVE 52

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 51.50 E-value: 1.92e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 154 EMLVQalYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11873   1 EVIVE--FDYDAEEPDELTLKVGDIITNVKKMEEGWWEGTLNGKRGMFPDNFVK 52

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); SH2D2A and SH7 both contain a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199830 Cd Length: 77 Bit Score: 52.14 E-value: 2.14e-09

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGdFSLSVKCPDGVQHFKV--LRDAQSKFFLWVVKFNSLNELVEYH 134
Cdd:cd10349   2 WFHGFITRREAERLLEPKPQGCYLVRFSESAVT-FVLSYRSRTCCRHFLLaqLRDGRHVVLGEDSAHARLQDLLLHY 77

Src homology 2 (SH2) domain found in Fyn; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198231 [Multi-domain] Cd Length: 101 Bit Score: 52.72 E-value: 2.26e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEK-LLS-NKHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWV-VKFNSLNEL 130
Cdd:cd10368   4 EWYFGKLGRKDAERqLLSfGNPRGTFLIRESETTKGAYSLSIRdwddmKGDHVKHYKIRKLDNGGYYITTrAQFETLQQL 83


                ....
gi 23344846 131 VEYH 134
Cdd:cd10368  84 VQHY 87

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212712 [Multi-domain] Cd Length: 51 Bit Score: 51.34 E-value: 2.31e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   1 MEAIakHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNY 52
Cdd:cd11778   2 VEAL--YDYEAQGDDEISIRVGDRIAVIRGDDGSGWTYGEINGVKGLFPTSY 51

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 51.48 E-value: 2.46e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11976   2 AKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVE 53

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212712 [Multi-domain] Cd Length: 51 Bit Score: 51.34 E-value: 2.51e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWN-GEIGNRKGIFPATY 205
Cdd:cd11778   2 VEALYDYEAQGDDEISIRVGDRIAVIRGDDGSGWTyGEINGVKGLFPTSY 51

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 51.14 E-value: 2.88e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDE-NWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11882   2 ARALYACKAEDESELSFEPGQIITNVQPSDEpGWLEGTLNGRTGLIPENYVEF 54

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 51.18 E-value: 2.97e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11874   3 KVLFSYTPQNEDELELKVGDTIEVLGEVEEGWWEGKLNGKVGVFPSNFVK 52

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212752 [Multi-domain] Cd Length: 50 Bit Score: 50.94 E-value: 3.24e-09

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATY 205
Cdd:cd11818   3 RALYDFTGENEDELSFKAGDIITELESIDEEWMSGELRGKSGIFPKNF 50

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212828 Cd Length: 58 Bit Score: 51.12 E-value: 3.37e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRS----DENWWNGEIGNRKGIFPATYV 206
Cdd:cd11895   1 LARALYSYTGQSPEELSFPEGALIRLLPRAqdgvDDGFWRGEFGGRVGVFPSLLV 55

Src homology 3 domain of Slit-Robo GTPase Activating Proteins; Slit-Robo GTPase Activating Proteins (srGAPs) are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. Vertebrates contain three isoforms of srGAPs (srGAP1-3), all of which are expressed during embryonic and early development in the nervous system but with different localization and timing. A fourth member has also been reported (srGAP4, also called ARHGAP4). srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212743 [Multi-domain] Cd Length: 53 Bit Score: 50.86 E-value: 3.59e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11809   4 AQFDYTGRSERELSFKKGDSLTLYRQVSDDWWRGQLNGQDGLVPHKYITL 53

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 51.16 E-value: 3.72e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 154 EMLVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTPYHS 211
Cdd:cd12060   1 QLVVKARFNFKQTNEDELSVCKGDIIYVTRVEEGGWWEGTLNGKTGWFPSNYVREIKS 58

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 50.73 E-value: 4.11e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11766   2 AVVKFNYEAQREDELSLRKGDRVLVLEKSSDGWWRGECNGQVGWFPSNYVTE 53

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212715 [Multi-domain] Cd Length: 53 Bit Score: 50.80 E-value: 4.24e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11781   1 KARALYPFKAQSAKELSLKKGDIIYIRR-QIDKNWYEGEHNGRVGIFPASYVEI 53

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 50.88 E-value: 4.45e-09

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11959   4 ALYDYQAADDDEISFDPDDIITNIEMIDEGWWRGVCRGKYGLFPANYV 51

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine kinase Bmx is expressed in the endothelium of large arteries, fetal endocardium, adult endocardium of the left ventricle, bone marrow, lung, testis, granulocytes, myeloid cell lines, and prostate cell lines. Bmx is involved in the regulation of Rho and serum response factor (SRF). Bmx has been shown to interact with PAK1, PTK2, PTPN21, and RUFY1. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains. It is not present in Txk and the type 1 splice form of the Drosophila homolog. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198262 Cd Length: 106 Bit Score: 51.88 E-value: 5.56e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLLSNK-HEGAFLIRISeSSPGDFSLSV-----KCPDG-VQHFKVLRDAQSKFFLWVVK-FNSLNEL 130
Cdd:cd10399   7 DWFAGNISRSQSEQLLRQKgKEGAFMVRNS-SQVGMYTVSLfskavNDKKGtVKHYHVHTNAENKLYLAENYcFDSIPKL 85


                ....*...
gi 23344846 131 VEYHRTAS 138
Cdd:cd10399  86 IHYHQHNS 93

Second Src Homology 3 domain (SH3B) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212988 [Multi-domain] Cd Length: 53 Bit Score: 50.38 E-value: 5.80e-09

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12055   3 QVAFSYLPQNEDELELKVGDIIEVVGEVEEGWWEGVLNGKTGMFPSNFI 51

Second Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212865 Cd Length: 57 Bit Score: 50.61 E-value: 6.46e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846 156 LVQALYDFVPQESGE------LDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11932   1 LCRALYNFDLKEKNReeskdcLKFQKDDIITVISRVDENWAEGKLGDQVGIFPILFV 57

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 50.32 E-value: 6.84e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11805   4 ALYDFNPQEPGELEFRRGDIITVLD-SSDPDWWKGELRGRVGIFPANYVQ 52

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Neural precursor cell Expressed, Developmentally Down-regulated 9; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212935 Cd Length: 57 Bit Score: 50.37 E-value: 7.32e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSD---ENWWNGEIGNRKGIFP 202
Cdd:cd12002   1 MARALYDNVPECAEELAFRKGDILTVIEQNTgglEGWWLCSLHGRQGIAP 50

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212778 Cd Length: 56 Bit Score: 50.04 E-value: 7.41e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSD---ENWWNGEIGNRKGIFPA 203
Cdd:cd11844   1 LARALYDNVAESPDELAFRRGDILTVLEQNTaglEGWWLCSLRGRQGIAPG 51

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of the Tec protein tyrosine kinase Btk is expressed in bone marrow, spleen, all hematopoietic cells except T lymphocytes and plasma cells where it plays a crucial role in B cell maturation and mast cell activation. Btk has been shown to interact with GNAQ, PLCG2, protein kinase D1, B-cell linker, SH3BP5, caveolin 1, ARID3A, and GTF2I. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. Two tyrosine phosphorylation (pY) sites have been identified in Btk: one located in the activation loop of the catalytic domain which regulates the transition between open (active) and closed (inactive) states and the other in its SH3 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198260 [Multi-domain] Cd Length: 106 Bit Score: 51.37 E-value: 7.88e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLLSNK-HEGAFLIRISeSSPGDFSLSVKCPDG------VQHFKVLRDAQSKFFLWVVK-FN 125
Cdd:cd10397   2 SLEMYEWYSKNMTRSQAEQLLKQEgKEGGFIVRDS-SKAGKYTVSVFAKSAgdpqgvIRHYVVCSTPQSQYYLAEKHlFS 80

                        90
                ....*....|....*....
gi 23344846 126 SLNELVEYHRTAS---VSR 141
Cdd:cd10397  81 TIPELINYHQHNAaglISR 99

Second Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212856 [Multi-domain] Cd Length: 57 Bit Score: 49.91 E-value: 8.60e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYV 206
Cdd:cd11923   5 AKYNFNADTNVELSLRKGDRVVLLKQVDQNWYEGKIpgTNRQGIFPVSYV 54

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 49.72 E-value: 8.96e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11959   2 AVALYDYQAADDDEISFDPDDIITNIEMIDEG-WWRGVCRGKYGLFPANYVEL 53

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 49.60 E-value: 9.99e-09

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11882   2 ARALYACKAEDESELSFEPGQIITNVQPSDEPGWLEGTLNGRTGLIPENYVE 53

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the N-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198191 Cd Length: 104 Bit Score: 51.24 E-value: 1.01e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLL--SNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFLWVVK-FNSLNELVEYHRT 136
Cdd:cd09938   3 FFYGSITREEAEEYLklAGMSDGLFLLRQSLRSLGGYVLSVCHGRKFHHYTIERQLNGTYAIAGGKaHCGPAELCEYHST 82


                ..
gi 23344846 137 AS 138
Cdd:cd09938  83 DL 84

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 49.57 E-value: 1.17e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIE 54
Cdd:cd11766   1 PAVVKFNYEAQREDELSLRKGDRVLVLEKSSDG-WWRGECNGQVGWFPSNYVT 52

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213017 [Multi-domain] Cd Length: 57 Bit Score: 49.80 E-value: 1.20e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMED---DSNWYRAELDGKEGLIPSNYI 53
Cdd:cd12141   4 AVYTFKARSPNELSVSANQRVRILEFSDltgNKEWWLAEANGQKGYVPSNYI 55

C-terminal Src Homology 3 domain of NADPH oxidase activator 1; Noxa1 is a homolog of p67phox and is a cytosolic subunit of the nonphagocytic NADPH oxidase complex Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Noxa1 is co-expressed with Nox1 in colon, stomach, uterus, prostate, and vascular smooth muscle cells, consistent with its regulatory role. It does not interact with p40phox, unlike p67phox, making Nox1 activity independent of p40phox, unlike Nox2. Noxa1 contains TPR, PB1, and C-terminal SH3 domains, but lacks the central SH3 domain that is present in p67phox. The TPR domain binds activated GTP-bound Rac. The C-terminal SH3 domain binds the polyproline motif found at the C-terminus of Noxo1, a homolog of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212980 Cd Length: 53 Bit Score: 49.43 E-value: 1.29e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12047   2 MVAQHDYSAQGPEDLEFSQGDTIDILSEVNQEWLEGHCDGRIGIFPKCFAVR 53

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 49.68 E-value: 1.31e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12061   1 VVRAKFNFQQTNEDELSFSKGDVIHVTRVEEGGWWEGTHNGRTGWFPSNYV 51

Src homology 2 (SH2) domain found in the Vav3 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav3 preferentially activates RhoA, RhoG and, to a lesser extent, Rac1. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. VAV3 has been shown to interact with Grb2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198270 Cd Length: 103 Bit Score: 50.77 E-value: 1.37e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVL-RD-----AQSKfflwvvKFNSLNELVEY 133
Cdd:cd10407   7 WYAGAMERLQAETELINRVNSTYLVRHRTKESGEYAISIKYNNEVKHIKILtRDgffhiAENR------KFKSLMELVEY 80

                        90
                ....*....|....*...
gi 23344846 134 HRTASVS---RSQDVKLR 148
Cdd:cd10407  81 YKHHSLKegfRSLDTTLQ 98

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 49.25 E-value: 1.38e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRK-GIFPATYV 206
Cdd:cd11825   2 VKALYDYRAQRPDELSFCKHAIITNVEKEDGGWWRGDYGGKKqKWFPANYV 52

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) and PACSIN 2; PACSIN 1 or Syndapin I (Synaptic dynamin-associated protein I) is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. PACSIN 2 or Syndapin II is expressed ubiquitously and is involved in the regulation of tubulin polymerization. It associates with Golgi membranes and forms a complex with dynamin II which is crucial in promoting vesicle formation from the trans-Golgi network. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212931 [Multi-domain] Cd Length: 56 Bit Score: 49.56 E-value: 1.43e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDEN-WWNGEI-GNRKGIFPATYVTP 208
Cdd:cd11998   3 VRALYDYDGQEQDELSFKAGDELTKLEDEDEQgWCKGRLdSGQVGLYPANYVEP 56

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 49.23 E-value: 1.44e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKIlNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11877   4 AKFNFEGTNEDELSFDKGDIITV-TQVVEGGWWEGTLNGKTGWFPSNYVK 52

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the third SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212714 [Multi-domain] Cd Length: 55 Bit Score: 49.22 E-value: 1.44e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRK--GIFPATYVTP 208
Cdd:cd11780   3 RALYSYTPQNEDELELREGDIVYVMEKCDDGWFVGTSERTGlfGTFPGNYVAR 55

Second Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212945 Cd Length: 62 Bit Score: 49.60 E-value: 1.49e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 23344846  13 ADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12012  20 AEEELPFKEGQLIKVYGDKDADGFYLGEINGRRGLVPCNMVS 61

Second Src homology 3 domain (or SH3B) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212923 [Multi-domain] Cd Length: 52 Bit Score: 49.27 E-value: 1.50e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSdENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11990   1 KAQALCSWTAKKDNHLNFSKNDIITVLEQQ-ENWWFGEVHGGRGWFPKSYVK 51

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing protein 2; ASAP2 is also called DDEF2 (Development and Differentiation Enhancing Factor 2), AMAP2, centaurin beta-3, or PAG3. It mediates the functions of Arf GTPases vial dual mechanisms: it exhibits GTPase activating protein (GAP) activity towards class I (Arf1) and II (Arf5) Arfs; and it binds class III Arfs (GTP-Arf6) stably without GAP activity. It binds paxillin and is implicated in Fcgamma receptor-mediated phagocytosis in macrophages and in cell migration. ASAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212899 Cd Length: 56 Bit Score: 49.18 E-value: 1.71e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIG---NRKGIFPATYV 206
Cdd:cd11966   2 VKALYNCVADNPDELTFSEGEIIIVDGEEDKEWWIGHIDgepTRRGAFPVSFV 54

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 49.34 E-value: 1.73e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSN-WYRAELDGKEGLIPSNYIE 54
Cdd:cd11842   1 KAVALYDFAGEQPGDLAFQKGDIITILKKSDSQNdWWTGRIGGREGIFPANYVE 54

Src Homology 3 domain of C-terminal Src kinase; CSK is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, CSK is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. CSK catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. It is expressed in a wide variety of tissues and plays a role, as a regulator of Src, in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. In addition, CSK also shows Src-independent functions. It is a critical component in G-protein signaling, and plays a role in cytoskeletal reorganization and cell migration. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212703 [Multi-domain] Cd Length: 57 Bit Score: 49.22 E-value: 1.85e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRS-DENWWNG--EIGnRKGIFPATYVT 207
Cdd:cd11769   6 AKYNFNGASEEDLPFKKGDILTIVAVTkDPNWYKAknKDG-REGMIPANYVQ 56

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 49.17 E-value: 1.96e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDEN-WWNGEIGNRKGIFPATYV 206
Cdd:cd11976   3 KARYDFCARDRSELSLKEGDIIKILNKKGQQgWWRGEIYGRVGWFPANYV 52

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70); ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198265 Cd Length: 105 Bit Score: 50.30 E-value: 1.99e-08

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLL--SNKHEGAFLIRISESSpGDFSLSVKCPDGVQHFKVLRDAQSKFFL-WVVKFNSLNELVEY 133
Cdd:cd10402  12 WYHGSIARDEAERRLysGAQPDGKFLLRERKES-GTYALSLVYGKTVYHYRIDQDKSGKYSIpEGTKFDTLWQLVEY 87

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 49.13 E-value: 1.99e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYV 206
Cdd:cd12057   3 KVLFPYEAQNEDELTIKEGDIVTLISKDciDAGWWEGELNGRRGVFPDNFV 53

Src Homology 3 domain of Small G protein Signaling Modulator 3; SGSM3 is also called Merlin-associated protein (MAP), RUN and SH3 domain-containing protein (RUSC3), RUN and TBC1 domain-containing protein 3 (RUTBC3), Rab GTPase-activating protein 5 (RabGAP5), or Rab GAP-like protein (RabGAPLP). It is expressed ubiquitously and functions as a regulator of small G protein RAP- and RAB-mediated neuronal signaling. It is involved in modulating NGF-mediated neurite outgrowth and differentiation. It also interacts with the tumor suppressor merlin and may play a role in the merlin-associated suppression of cell growth. SGSM3 contains TBC, SH3, and RUN domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212747 Cd Length: 53 Bit Score: 49.03 E-value: 2.05e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11813   3 KALLDFERHDDDELGFRKNDIITIISQKDEHCWVGELNGLRGWFPAKFV 51

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212881 [Multi-domain] Cd Length: 54 Bit Score: 49.04 E-value: 2.06e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTD-RSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11948   4 ALYSFQATESDELPFQKGDILKILNmEDDQNWYKAELQGREGYIPKNYI 52

Src homology 2 (SH2) domain found in Yes; Yes is a member of the Src non-receptor type tyrosine kinase family of proteins. Yes is the cellular homolog of the Yamaguchi sarcoma virus oncogene. In humans it is encoded by the YES1 gene which maps to chromosome 18 and is in close proximity to thymidylate synthase. A corresponding Yes pseudogene has been found on chromosome 22. YES1 has been shown to interact with Janus kinase 2, CTNND1,RPL10, and Occludin. Yes1 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198229 Cd Length: 101 Bit Score: 50.40 E-value: 2.11e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLLSN--KHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLR-DAQSKFFLWVVKFNSLNEL 130
Cdd:cd10366   4 EWYFGKMGRKDAERLLLNpgNQRGIFLVRESETTKGAYSLSIRdwdevRGDNVKHYKIRKlDNGGYYITTRAQFDTLQKL 83


                ....
gi 23344846 131 VEYH 134
Cdd:cd10366  84 VKHY 87

Second Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212855 [Multi-domain] Cd Length: 58 Bit Score: 49.22 E-value: 2.13e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIG--NRKGIFPATYV 206
Cdd:cd11922   5 AKFNFNGDTQVEMSFRKGERITLLRQVDENWYEGRIPgtSRQGIFPITYV 54

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 48.88 E-value: 2.20e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE----IGNRK-GIFPATYVTP 208
Cdd:cd11887   3 KVKALYPYESDHEDDLNFDVGQLITVTEEEDADWYFGEyvdsNGNTKeGIFPKNFVEV 60

Third Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212750 [Multi-domain] Cd Length: 51 Bit Score: 48.56 E-value: 2.36e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11816   4 ARFDFEGEQEDELSFSEGDVITLKEYVGEEWAKGELNGKIGIFPLNFV 51

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212893 [Multi-domain] Cd Length: 54 Bit Score: 48.93 E-value: 2.39e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYVT 207
Cdd:cd11960   2 ARALYDYQAADDTEISFDPGDIITDIEQIDEGWWRGTGPDgTYGLFPANYVE 53

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 48.46 E-value: 2.64e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11819   2 AKALYDYQAAEDNEISFVEGDIITQIEQIDEGWWLGVNAKGQKGLFPANYVEL 54

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 48.54 E-value: 2.65e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11806   4 AIADFVATDDSQLSFESGDKLLVLRKPSVDWWWAEHNGCCGYIPASHLHQ 53

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 48.48 E-value: 3.02e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDEN-WWNGEIGNRKGIFPATYV 206
Cdd:cd11978   5 ARYDFCARDMRELSLLKGDVVKIYTKMSTNgWWRGEVNGRVGWFPSTYV 53

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor; ASEF, also called ARHGEF4, exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli). GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF can activate Rac1 or Cdc42. Truncated ASEF, which is found in colorectal cancers, is constitutively active and has been shown to promote angiogenesis and cancer cell migration. ASEF contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212906 [Multi-domain] Cd Length: 73 Bit Score: 49.25 E-value: 3.03e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11973  21 EALWDHVTMDDQELGFKAGDVIEVMDATNKEWWWGRVLDSEGWFPASFV 69

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 48.47 E-value: 3.08e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11826   3 VALYDYTADKDDELSFQEGDIIYVTKKNDD-GWYEGVLNGVTGLFPGNYVE 52

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 48.38 E-value: 3.13e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 23344846     5 AKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESED-GWWEGINTGRTGLVPANYVE 49

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199829 Cd Length: 99 Bit Score: 49.66 E-value: 3.22e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRIT--RADAEKLLS---NKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKV---LRDAQSKFFLWVVK-FNSLNEL 130
Cdd:cd10341   6 WFHGKLGdgRDEAEKLLLeycEGGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIrsrQENGEKKYYLTDNLvFDSLYEL 85


                ....*
gi 23344846 131 VEYHR 135
Cdd:cd10341  86 IDYYR 90

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 48.52 E-value: 3.25e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRsDENWWNGEI-GNRKGIFPATYVTP 208
Cdd:cd11837   2 ATALYPWRAKKENHLSFAKGDIITVLEQ-QEMWWFGELeGGEEGWFPKSYVKE 53

First Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212854 Cd Length: 55 Bit Score: 48.38 E-value: 3.30e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 161 YDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11921   7 FDFQAQSPKELTLQKGDIVYIHKEVDKNWLEGEHHGRVGIFPANYV 52

Src Homology 3 domain of TXK, also called Resting lymphocyte kinase (Rlk); TXK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. Rlk is expressed in T-cells and mast cell lines, and is a key component of T-cell receptor (TCR) signaling. It is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212840 [Multi-domain] Cd Length: 55 Bit Score: 48.41 E-value: 3.69e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNG--EIGNrKGIFPATYVT 207
Cdd:cd11907   3 VKALYDFLPREPSNLALKRAEEYLILEQYDPHWWKArdRYGN-EGLIPSNYVT 54

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 48.43 E-value: 3.89e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 157 VQALYDFVP-QESGELDFRRGDVITVTDRSDE-----NWWNGEIGN-RKGIFPATYVT 207
Cdd:cd11771   2 CRALYDFTPeNPEMELSLKKGDIVAVLSKTDPlgrdsEWWKGRTRDgRIGWFPSNYVE 59

Src Homology 3 domain of the p40phox subunit of NADPH oxidase; p40phox, also called Neutrophil cytosol factor 4 (NCF-4), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. It contains an N-terminal PX domain, a central SH3 domain, and a C-terminal PB1 domain that interacts with p67phox. The SH3 domain of p40phox binds to canonical polyproline and noncanonical motifs at the C-terminus of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212802 Cd Length: 54 Bit Score: 48.26 E-value: 4.01e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11869   3 EALFDFTGNSKLELNFKAGDVIFLLSRVNKDWLEGTVRGATGIFPLSFV 51

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 48.23 E-value: 4.26e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11820   5 ALYDFEAAEDNELTFKAGEIITVLD-DSDPNWWKGSNHRGEGLFPANFV 52

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 48.10 E-value: 4.36e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11978   3 AIARYDFCARDMRELSLLKGDVVKIYTKMSTNGWWRGEVNGRVGWFPSTYVE 54

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 47.90 E-value: 4.44e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIE 54
Cdd:cd11950   2 VRALYDFEALEDDELGFNSGDVIEVLDSSNPS-WWKGRLHGKLGLFPANYVA 52

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212932 [Multi-domain] Cd Length: 56 Bit Score: 48.01 E-value: 4.49e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVIT-VTDRSDENW-WNGEIGNRKGIFPATYV 206
Cdd:cd11999   4 VRAVYDYTGQEPDELSFKAGEELLkVEDEDEQGWcKGVTDGGAVGLYPANYV 55

Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212887 [Multi-domain] Cd Length: 57 Bit Score: 48.09 E-value: 4.91e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDE---NWWNGEIGNRKGIFP 202
Cdd:cd11954   2 MVYALWDYEAQNADELSFQEGDAITILRRKDDsetEWWWARLNDKEGYVP 51

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212933 Cd Length: 57 Bit Score: 47.95 E-value: 5.09e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846 155 MLVQALYDFVPQESGELDFRRGDVITVTDRS---DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12000   1 LLARALYDNKADCSDELAFRRGDILTVLEQNvpgSEGWWKCLLHGRQGLAPANRLQL 57

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 47.74 E-value: 5.38e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTD-RSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11804   4 AKHDFKATAEDELSFKKGSILKVLNmEDDPNWYKAELDGKEGLIPKNYI 52

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 47.97 E-value: 5.41e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 161 YDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12052   6 FDYKAQHEDELTITVGDIITKIKKDDGGWWEGEIKGRRGLFPDNFV 51

First Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212707 [Multi-domain] Cd Length: 57 Bit Score: 47.80 E-value: 5.47e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWW-------NGEIGNRKGIFPATY 205
Cdd:cd11773   1 VYKALYDYEPQTEDELTIQEDDILYLLEKSDDDWWkvklkvnSSDDDEPVGLVPATY 57

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 47.71 E-value: 5.70e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAE-LDGKEGLIPSNYIE 54
Cdd:cd11763   4 ALYDFDSQPSGELSLRAGEVLTITRQDVGDGWLEGRnSRGEVGLFPSSYVE 54

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 47.64 E-value: 5.92e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11964   5 AIYDFEAAEDNELTFKAGDIITILD-DSDPNWWKGETPQGTGLFPSNFV 52

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 47.65 E-value: 6.17e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIE 54
Cdd:cd11873   1 EVIVEFDYDAEEPDELTLKVGDIITNVKKMEEG-WWEGTLNGKRGMFPDNFVK 52

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212704 [Multi-domain] Cd Length: 54 Bit Score: 47.69 E-value: 6.90e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGNRkGIFPATYV 206
Cdd:cd11770   1 LYEALSDFQAEQEGDLSFKKGEVLRIISKRADGWWLAEnsKGNR-GLVPKTYL 52

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 47.64 E-value: 7.11e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11803   5 ALYDFEPENEGELGFKEGDIITLTNQIDE-NWYEGMVNGQSGFFPVNYVE 53

Second Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212857 Cd Length: 56 Bit Score: 47.65 E-value: 7.43e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIG--NRKGIFPATYV 206
Cdd:cd11924   5 AQYTFKGDLEVELSFRKGEHICLIRKVNENWYEGRITgtGRQGIFPASYV 54

Third Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212858 Cd Length: 57 Bit Score: 47.68 E-value: 7.50e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYVTP 208
Cdd:cd11925   5 ALYAYKPQKNDELELRKGEMYRVIEKCQDGWFKGTSlrTGVSGVFPGNYVTP 56

Second Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212749 [Multi-domain] Cd Length: 52 Bit Score: 47.18 E-value: 7.92e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846 160 LYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11815   5 LHDFPAEHSDDLSLNSGEIVYLLEKIDTEWYRGKCKNTTGIFPANHV 51

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212704 [Multi-domain] Cd Length: 54 Bit Score: 47.31 E-value: 7.97e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11770   3 EALSDFQAEQEGDLSFKKGEVLRIISKRADGWWLAENSKGNRGLVPKTYLKV 54

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212908 Cd Length: 62 Bit Score: 47.40 E-value: 8.54e-08

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11975   8 EAVWDHVTMANRELAFKAGDVIKVLDASNKDWWWGQIDDEEGWFPASFV 56

Src homology 2 (SH2) domain found in B lymphoid kinase (Blk); Blk is a member of the Src non-receptor type tyrosine kinase family of proteins. Blk is expressed in the B-cells. Unlike most other Src members Blk lacks cysteine residues in the SH4 domain that undergo palmitylation. Blk is required for the development of IL-17-producing gamma-delta T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny. Blk has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198234 [Multi-domain] Cd Length: 100 Bit Score: 48.48 E-value: 8.66e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLL---SNKhEGAFLIRISESSPGDFSLSVK--CPDG--VQHFKVLRDAQSKFFLWV-VKFNSLNELV 131
Cdd:cd10371   5 WFFRTISRKDAERQLlapMNK-AGSFLIRESESNKGAFSLSVKdvTTQGevVKHYKIRSLDNGGYYISPrITFPTLQALV 83


                ...
gi 23344846 132 EYH 134
Cdd:cd10371  84 QHY 86

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) family; STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated by a receptor. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. The CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198175 Cd Length: 115 Bit Score: 48.73 E-value: 8.76e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLR 111
Cdd:cd09919  21 LIMGFISKEEAEDLLKKKPPGTFLLRFSDSELGGITIAWVNEDPDGQSQVIH 72

Third (or C-terminal) Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212851 [Multi-domain] Cd Length: 58 Bit Score: 47.26 E-value: 8.83e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNG--EIGNRKGIFPATYVTP 208
Cdd:cd11918   5 KAVYQYRPQNEDELELREGDRVDVMQQCDDGWFVGvsRRTQKFGTFPGNYVAP 57

Src homology 3 domain of RUN and SH3 domain-containing protein 2; RUSC2, also called Iporin or Interacting protein of Rab1, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. RUSC proteins are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212890 Cd Length: 52 Bit Score: 47.22 E-value: 8.97e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11957   2 VKALCHHIATEPGQLSFNKGDILQVLSRADGDWLRCSLGPDSGLVPIAYVT 52

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Embryonal Fyn-associated Substrate; EFS is also called HEFS, CASS3 (Cas scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212936 Cd Length: 62 Bit Score: 47.58 E-value: 9.65e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDEN---WWNGEIGNRKGIFPATYV 206
Cdd:cd12003   2 LAKALYDNAAESPEELSFRRGDVLMVLKREHGSlpgWWLCSLHGQQGIAPANRL 55

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212895 [Multi-domain] Cd Length: 54 Bit Score: 47.10 E-value: 9.98e-08

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYV 206
Cdd:cd11962   3 VVLYDYEKDEDNEIELVEGEIVTNIEMVDEDWWMGTNSKgESGLFPSNYV 52

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 47.13 E-value: 1.01e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMED-DSNWYRAELDGKEGLIPSNYI 53
Cdd:cd12056   6 ALFHYEGTNEDELDFKEGEIILIISKDTgEPGWWKGELNGKEGVFPDNFV 55

N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general the longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the N-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198216 Cd Length: 103 Bit Score: 48.29 E-value: 1.16e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAE-KLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRdAQSKFFLWVVKFNSLNELVEYHRTAS 138
Cdd:cd10353  21 WYHGRLDRTIAEeRLRQAGKLGSYLIRESDRRPGSFVLSFLSRTGVNHFRIIA-MCGDYYIGGRRFSSLSDLIGYYSHVS 99

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212850 [Multi-domain] Cd Length: 61 Bit Score: 47.29 E-value: 1.18e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRK--GIFPATYV 206
Cdd:cd11917   8 QALYNYMPRNEDELELREGDVIDVMEKCDDGWFVGTSRRTKffGTFPGNYV 58

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 46.95 E-value: 1.20e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI---GNRK--GIFPATYV 206
Cdd:cd11839   1 IAQVIAPFTATAENQLSLAVGQLVLVRKKSPSGWWEGELqarGKKRqiGWFPANYV 56

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212910 [Multi-domain] Cd Length: 58 Bit Score: 46.93 E-value: 1.25e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDR--SDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11977   5 ARYNFAARDMRELSLREGDVVRIYSRigGDQGWWKGETNGRIGWFPSTYV 54

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212751 [Multi-domain] Cd Length: 50 Bit Score: 46.70 E-value: 1.30e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNY 52
Cdd:cd11817   2 AVALYDFTGETEEDLSFQRGDRILVTE-HLDAEWSRGRLNGREGIFPRAF 50

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 46.97 E-value: 1.30e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVtDRSDEN---WWNGEIGNRKGIFPATYV 206
Cdd:cd11836   3 RALYAFEARNPDEISFQPGDIIQV-DESQVAepgWLAGELKGKTGWFPANYV 53

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 46.59 E-value: 1.37e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILkILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11786   2 AKALYNYEGKEPGDLSFKKGDII-LLRKRIDENWYHGECNGKQGFFPASYVQ 52

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 46.48 E-value: 1.52e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11856   3 VAIADYEAQGDDEISLQEGEVVEVLE-KNDSGWWYVRKGDKEGWVPASYLE 52

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 46.56 E-value: 1.61e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE-IGN-RKGIFPATYVT 207
Cdd:cd11793   2 VQCVHAYTAQQPDELTLEEGDVVNVLRKMPDGWYEGErLRDgERGWFPSSYTE 54

Src homology 3 domain of SH3 protein interacting with Nck, 90 kDa (SPIN90); SPIN90 is also called NCK interacting protein with SH3 domain (NCKIPSD), Dia-interacting protein (DIP), 54 kDa vimentin-interacting protein (VIP54), or WASP-interacting SH3-domain protein (WISH). It is an F-actin binding protein that regulates actin polymerization and endocytosis. It associates with the Arp2/3 complex near actin filaments and determines filament localization at the leading edge of lamellipodia. SPIN90 is expressed in the early stages of neuronal differentiation and plays a role in regulating growth cone dynamics and neurite outgrowth. It also interacts with IRSp53 and regulates cell motility by playing a role in the formation of membrane protrusions. SPIN90 contains an N-terminal SH3 domain, a proline-rich domain, and a C-terminal VCA (verprolin-homology and cofilin-like acidic) domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212783 [Multi-domain] Cd Length: 53 Bit Score: 46.54 E-value: 1.69e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWN-GEIGNRKGIFPATYVT 207
Cdd:cd11849   1 MYRALYDFKSAEPNTLSFSEGETFLLLERSNAHWWLvTNHSGETGYVPANYVK 53

Src homology 2 (SH2) domain found in Fyn isoform b like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform b type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198282 Cd Length: 101 Bit Score: 47.75 E-value: 1.77e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEK-LLS-NKHEGAFLIRISESSPGDFSLSVK-----CPDGVQHFKVLRDAQSKFFLWV-VKFNSLNELV 131
Cdd:cd10419   5 WYFGKLGRKDAERqLLSfGNPRGTFLIRESETTKGAYSLSIRdwddmKGDHVKHYKIRKLDNGGYYITTrAQFETLQQLV 84


                ...
gi 23344846 132 EYH 134
Cdd:cd10419  85 QHY 87

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in its carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198211 Cd Length: 86 Bit Score: 47.03 E-value: 2.08e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  59 DWYYGRITRADAEKLLSNKH--EGAFLIRISESSPGDFSLSVKCPDGVQHFKVlRDAQSKFF------LWvvkfNSLNEL 130
Cdd:cd10348   1 QWLHGALDRNEAVEILKQKAdaDGSFLVRYSRRRPGGYVLTLVYENHVYHFEI-QNRDDKWFyiddgpYF----ESLEHL 75


                ....
gi 23344846 131 VEYH 134
Cdd:cd10348  76 IEHY 79

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) and PACSIN 2; PACSIN 1 or Syndapin I (Synaptic dynamin-associated protein I) is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. PACSIN 2 or Syndapin II is expressed ubiquitously and is involved in the regulation of tubulin polymerization. It associates with Golgi membranes and forms a complex with dynamin II which is crucial in promoting vesicle formation from the trans-Golgi network. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212931 [Multi-domain] Cd Length: 56 Bit Score: 46.48 E-value: 2.14e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD-GKEGLIPSNYIE 54
Cdd:cd11998   5 ALYDYDGQEQDELSFKAGDELTKLEDEDEQGWCKGRLDsGQVGLYPANYVE 55

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 46.17 E-value: 2.22e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11963   6 ALYDFEAVEDNELTFKHGEIIIVLD-DSDANWWKGENHRGVGLFPSNFV 53

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 46.21 E-value: 2.41e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIE 54
Cdd:cd11824   1 KYSVLYDYTAQEDDELSISKGDVVAVIEKGEDG-WWTVERNGQKGLVPGTYLE 52

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 45.92 E-value: 2.47e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   8 DFSATADDELSFRKTQILKILNME-DDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12142   7 DYNPVAPDELALKKGDVIEVISKEtEDEGWWEGELNGRRGFFPDNFVMP 55

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 46.22 E-value: 2.51e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEdDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd12061   4 AKFNFQQTNEDELSFSKGDVIHVTRVE-EGGWWEGTHNGRTGWFPSNYV 51

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing protein 1; ASAP1 is also called DDEF1 (Development and Differentiation Enhancing Factor 1), AMAP1, centaurin beta-4, or PAG2. an Arf GTPase activating protein (GAP) with activity towards Arf1 and Arf5 but not Arf6. However, it has been shown to bind GTP-Arf6 stably without GAP activity. It has been implicated in cell growth, migration, and survival, as well as in tumor invasion and malignancy. It binds paxillin and cortactin, two components of invadopodia which are essential for tumor invasiveness. It also binds focal adhesion kinase (FAK) and the SH2/SH3 adaptor CrkL. ASAP1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212898 [Multi-domain] Cd Length: 57 Bit Score: 46.15 E-value: 2.69e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIG---NRKGIFPATYV 206
Cdd:cd11965   2 VKTIYDCQADNDDELTFVEGEVIIVTGEEDQEWWIGHIEgqpERKGVFPVSFV 54

Src homology 3 domain of Alpha Spectrin; Spectrin is a major structural component of the red blood cell membrane skeleton and is important in erythropoiesis and membrane biogenesis. It is a flexible, rope-like molecule composed of two subunits, alpha and beta, which consist of many spectrin-type repeats. Alpha and beta spectrin associate to form heterodimers and tetramers; spectrin tetramer formation is critical for red cell shape and deformability. Defects in alpha spectrin have been associated with inherited hemolytic anemias including hereditary spherocytosis (HSp), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP). Alpha spectrin contains a middle SH3 domain and a C-terminal EF-hand binding motif in addition to multiple spectrin repeats. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212742 [Multi-domain] Cd Length: 53 Bit Score: 45.94 E-value: 2.77e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11808   1 CVVALYDYQEKSPREVSMKKGDILTLLNSSNKDWWKVEVNDRQGFVPAAYV 51

Src homology 2 (SH2) domain found in SH2 domain-bearing protein kinases D and E (ShkD and ShkE); SH2-bearing genes cloned from Dictyostelium include two transcription factors, STATa and STATc, and a signaling factor, SHK1 (shkA). A database search of the Dictyostelium discoideum genome revealed two additional putative STAT sequences, dd-STATb and dd-STATd, and four additional putative SHK genes, dd-SHK2 (shkB), dd-SHK3 (shkC), dd-SHK4 (shkD), and dd-SHK5 (shkE). This model contains members of shkD and shkE. All of the SHK members are most closely related to the protein kinases found in plants. However these kinases in plants are not conjugated to any SH2 or SH2-like sequences. Alignment data indicates that the SHK SH2 domains carry some features of the STAT SH2 domains in Dictyostelium. When STATc's linker domain was used for a BLAST search, the sequence between the protein kinase domain and the SH2 domain (the linker) of SHK was recovered, suggesting a close relationship among these molecules within this region. SHK's linker domain is predicted to contain an alpha-helix which is indeed homologous to that of STAT. Based on the phylogenetic alignment, SH2 domains can be grouped into two categories, STAT-type and Src-type. SHK family members are in between, but are closer to the STAT-type which indicates a close relationship between SHK and STAT families in their SH2 domains and further supports the notion that SHKs linker-SH2 domain evolved from STAT or STATL (STAT-like Linker-SH2) domain found in plants. In SHK, STAT, and SPT6, the linker-SH2 domains all reside exclusively in the C-terminal regions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198220 Cd Length: 87 Bit Score: 46.73 E-value: 2.80e-07

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGD--FSLSVKCPDGVQHFKVLRDAQSKF 117
Cdd:cd10357  12 WFHGDISRDEAEKRLRGRPEGTFLIRLSSTDPKKtpFTISKKKKSKPVHKRISRIDVNNY 71

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 45.80 E-value: 3.12e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11823   4 ALYSYTANREDELSLQPGDIIEVHEKQDD-GWWLGELNGKKGIFPATYVE 52

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 45.75 E-value: 3.58e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGI-FPATYV 206
Cdd:cd11970   6 VKALFDYKAQREDELTFTKNAIIQNVEKQEGGWWRGDYGGKKQLwFPSNYV 56

Src homology 3 domain of SH3 and multiple ankyrin repeat domains (Shank) proteins; Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. They bind a variety of membrane and cytosolic proteins, and exist in alternatively spliced isoforms. They are highly enriched in postsynaptic density (PSD) where they interact with the cytoskeleton and with postsynaptic membrane receptors including NMDA and glutamate receptors. They are crucial in the construction and organization of the PSD and dendritic spines of excitatory synapses. There are three members of this family (Shank1, Shank2, Shank3) which show distinct and cell-type specific patterns of expression. Shank1 is brain-specific; Shank2 is found in neurons, glia, endocrine cells, liver, and kidney; Shank3 is widely expressed. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212766 Cd Length: 50 Bit Score: 45.50 E-value: 3.63e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPAT 204
Cdd:cd11832   4 AVKSYSPQEEGEISLHKGDRVKVLSIGEGGFWEGSVRGRTGWFPSD 49

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 3 (PACSIN3); PACSIN 3 or Syndapin III (Synaptic dynamin-associated protein III) is expressed ubiquitously and regulates glucose uptake in adipocytes through its role in GLUT1 trafficking. It also modulates the subcellular localization and stimulus-specific function of the cation channel TRPV4. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212930 [Multi-domain] Cd Length: 56 Bit Score: 45.72 E-value: 3.73e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRG-DVITVTDRSDENWWNGEIGN-RKGIFPATYV 206
Cdd:cd11997   4 VRALYDYTGQEADELSFKAGeELLKIGEEDEQGWCKGRLLSgRIGLYPANYV 55

Third Src Homology 3 domain of Nck adaptor proteins; This group contains the third SH3 domain of Nck, the first SH3 domain of Caenorhabditis elegans Ced-2 (Cell death abnormality protein 2), and similar domains. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. Ced-2 is a cell corpse engulfment protein that interacts with Ced-5 in a pathway that regulates the activation of Ced-10, a Rac small GTPase.

Pssm-ID: 212701 [Multi-domain] Cd Length: 56 Bit Score: 45.38 E-value: 3.89e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNM-EDDSNWYRAE-LDGKEGLIPSNYIE 54
Cdd:cd11767   1 VVVALYPFTGENDEELSFEKGERLEIIEKpEDDPDWWKARnALGTTGLVPRNYVE 55

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 45.60 E-value: 3.98e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11949   4 ALFDFDPQEDGELGFRRGDFIEVMD-NSDPNWWKGACHGQTGMFPRNYVT 52

Second Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212856 [Multi-domain] Cd Length: 57 Bit Score: 45.68 E-value: 4.05e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILkILNMEDDSNWYRAELDG--KEGLIPSNYIEM 55
Cdd:cd11923   2 EAVAKYNFNADTNVELSLRKGDRV-VLLKQVDQNWYEGKIPGtnRQGIFPVSYVEV 56

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 3 (PACSIN3); PACSIN 3 or Syndapin III (Synaptic dynamin-associated protein III) is expressed ubiquitously and regulates glucose uptake in adipocytes through its role in GLUT1 trafficking. It also modulates the subcellular localization and stimulus-specific function of the cation channel TRPV4. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212930 [Multi-domain] Cd Length: 56 Bit Score: 45.34 E-value: 4.21e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAEL-DGKEGLIPSNYIE 54
Cdd:cd11997   6 ALYDYTGQEADELSFKAGEELLKIGEEDEQGWCKGRLlSGRIGLYPANYVE 56

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212734 [Multi-domain] Cd Length: 57 Bit Score: 45.44 E-value: 4.31e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSN---WYRAELDGKEGLIPSNYI 53
Cdd:cd11800   3 YALYTFEARSPGELSVTEGQVVTVLEKHDLKGnpeWWLVEDRGKQGYVPSNYL 55

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 45.27 E-value: 4.33e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd12052   1 EAIVEFDYKAQHEDELTITVGDIITKIK-KDDGGWWEGEIKGRRGLFPDNFV 51

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 45.18 E-value: 4.62e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEdDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11951   4 AQYDFSAEDPSQLSFRRGDIIEVLDCP-DPNWWRGRISGRVGFFPRNYV 51

Src homology 3 domain of Blk Protein Tyrosine Kinase; Blk is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. It is expressed specifically in B-cells and is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212942 [Multi-domain] Cd Length: 54 Bit Score: 45.19 E-value: 4.77e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAE--LDGKEGLIPSNYI 53
Cdd:cd12009   3 IAQYDFVPSNERDLQLKKGEKLQVL--KSDGEWWLAKslTTGKEGYIPSNYV 52

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Embryonal Fyn-associated Substrate; EFS is also called HEFS, CASS3 (Cas scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212936 Cd Length: 62 Bit Score: 45.27 E-value: 4.97e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDS--NWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12003   3 AKALYDNAAESPEELSFRRGDVLMVLKREHGSlpGWWLCSLHGQQGIAPANRLRL 57

Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein family has 3 members: SH2B1 (SH2-B, PSM), SH2B2 (APS), and SH2B3 (Lnk). SH2B family members contain a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198209 Cd Length: 97 Bit Score: 46.26 E-value: 5.08e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLL----SNKHeGAFLIRISESSPGDFSLSVKCPDGVQHFK--VLRDAQSKF-FLWvvkFNS 126
Cdd:cd10346   4 ELSEYPWFHGTLSRSDAAQLVlhsgADGH-GVFLVRQSETRRGEFVLTFNFQGRAKHLRltLNEKGQCRVqHLW---FPS 79

                        90
                ....*....|
gi 23344846 127 LNELVEYHRT 136
Cdd:cd10346  80 IFDMLEHFRQ 89

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 45.08 E-value: 5.46e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMED---DSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11762   4 ALYDYEAQSDEELSFPEGAIIRILRKDDngvDDGWWEGEFNGRVGVFPSLVVE 56

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212827 Cd Length: 56 Bit Score: 45.31 E-value: 5.56e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDR---SDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11894   2 VKALYDYEGQTDDELSFPEGAIIRILNKenqDDDGFWEGEFNGRIGVFPSVLV 54

Src homology 3 domains of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212785 Cd Length: 62 Bit Score: 45.38 E-value: 5.74e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 23344846  12 TADDELSFRKTQILKILNMEDDSNWYRAEL-DGKEGLIPSNYIE 54
Cdd:cd11851  18 DPEEELSFHAGDVVRVYGPMDEDGFYYGELeGGRKGLVPSNFVQ 61

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 45.09 E-value: 6.23e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDEnWWNGEIGNRKGIFPATYV 206
Cdd:cd11989   3 QALYPWRAKKDNHLNFNKNDVITVLEQQDM-WWFGEVQGQKGWFPKSYV 50

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212717 [Multi-domain] Cd Length: 55 Bit Score: 45.08 E-value: 6.28e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGNRKGIFPATYVTP 208
Cdd:cd11783   4 ALYPYKPQKPDELELRKGEMYTVTEKCQDGWFKGTslRTGQSGVFPGNYVQP 55

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 44.82 E-value: 6.39e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11961   2 AKALYDYDAAEDNELSFFENDKIINIEFVDD-DWWLGECHGSRGLFPSNYVEL 53

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 44.89 E-value: 7.11e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 23344846     3 AIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:pfam07653   2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDND-GWWEGETGGRVGLVPSTAVE 52

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 (Cyk3 or Cyk3p) is a component of the actomyosin ring independent cytokinesis pathway in yeast. It interacts with Inn1 and facilitates its recruitment to the bud neck, thereby promoting cytokinesis. Cyk3p contains an N-terminal SH3 domain and a C-terminal transglutaminase-like domain. The Cyk3p SH3 domain binds to the C-terminal proline-rich region of Inn1. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212822 Cd Length: 53 Bit Score: 44.80 E-value: 7.57e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRK--GIFPATYV 206
Cdd:cd11889   2 VKAVYSWAGETEGDLGFLEGDLIEVLSIGDGSWWSGKLRRNGaeGIFPSNFV 53

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212741 [Multi-domain] Cd Length: 57 Bit Score: 44.68 E-value: 7.89e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDS--NWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11807   5 ALFDYEAENGDELSFREGDELTVLRKGDDDetEWWWARLNDKEGYVPRNLLGL 57

First Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the first C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212845 [Multi-domain] Cd Length: 55 Bit Score: 44.52 E-value: 8.15e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDSNWYRAELD-GKEGLIPSNYIEM 55
Cdd:cd11912   7 DYTASGDDEVSISEGEEVTVLEPDDGSGWTKVRNGsGEEGLVPTSYIEI 55

First Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212707 [Multi-domain] Cd Length: 57 Bit Score: 44.72 E-value: 8.64e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDsNWYRAEL-------DGKEGLIPSNY 52
Cdd:cd11773   4 ALYDYEPQTEDELTIQEDDILYLLEKSDD-DWWKVKLkvnssddDEPVGLVPATY 57

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212800 Cd Length: 53 Bit Score: 44.34 E-value: 9.14e-07

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDS-NWYRAELDGKEGLIPSNYI 53
Cdd:cd11866   7 DCSGNEPDELSFKRGDLIYIISKEYDSfGWWVGELNGKVGLVPKDYL 53

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member of the Tec protein tyrosine kinase Itk is expressed thymus, spleen, lymph node, T lymphocytes, NK and mast cells. It plays a role in T-cell proliferation and differentiation, analogous to Tec family kinases Txk. Itk has been shown to interact with Fyn, Wiskott-Aldrich syndrome protein, KHDRBS1, PLCG1, Lymphocyte cytosolic protein 2, Linker of activated T cells, Karyopherin alpha 2, Grb2, and Peptidylprolyl isomerase A. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198259 Cd Length: 108 Bit Score: 45.94 E-value: 9.52e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  58 HDWYYGRITRADAEKLL-SNKHEGAFLIRISeSSPGDFSLSVKCPDGVQ--------HFKVLRDAQSKFFLwVVK--FNS 126
Cdd:cd10396   6 YEWYNKNINRSKAEKLLrDEGKEGGFMVRDS-SQPGLYTVSLYTKAGGEgnpcirhyHIKETNDSPKKYYL-AEKhvFNS 83


                ....*....
gi 23344846 127 LNELVEYHR 135
Cdd:cd10396  84 IPELIEYHK 92

Third Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212837 [Multi-domain] Cd Length: 57 Bit Score: 44.63 E-value: 9.73e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDR--SDENWW-----NGEIgnrkGIFPATYVT 207
Cdd:cd11904   2 VVQALYPFSSSNDEELNFEKGEVMDVIEKpeNDPEWWkcrkaNGQV----GLVPKNYVT 56

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. Its N-terminal SH3 domain binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212879 [Multi-domain] Cd Length: 56 Bit Score: 44.63 E-value: 9.92e-07

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 155 MLVQALYDFVPQESGELDFRRGDVITV-TDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11946   1 MEAIAKYDFKATADDELSFKRGDILKVlNEECDQNWYKAELNGKDGFIPKNYI 53

Second Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212863 Cd Length: 55 Bit Score: 44.21 E-value: 1.07e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDFVPQESGE----LDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11930   3 KALYDFEVKDKEAdkdcLPFAKDDILTVIRRVDENWAEGMLGDKIGIFPISYV 55

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb10 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198278 Cd Length: 108 Bit Score: 45.78 E-value: 1.08e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  56 KNHDWYYGRITRADAEKLLSNKH--EGAFLIRISESSPGDFSLSVKCPDGVQHFKVL---RDAQSKFFL--WVVKFNSLN 128
Cdd:cd10415   3 RTQHWFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpceDDGQTFFSLddGNTKFSDLI 82


                ....*..
gi 23344846 129 ELVEYHR 135
Cdd:cd10415  83 QLVDFYQ 89

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212905 [Multi-domain] Cd Length: 61 Bit Score: 44.23 E-value: 1.21e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIEMKNH 58
Cdd:cd11972   4 KVVAIYDYTKDKEDELSFQEGAIIYVIKKNDDG-WYEGVMNGVTGLFPGNYVESIMH 59

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb7 is part of the Grb7 family of proteins which also includes Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198276 Cd Length: 108 Bit Score: 45.67 E-value: 1.22e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  56 KNHDWYYGRITRADAEKLLSNKH--EGAFLIRISESSPGDFSLSVKCPDGVQHFKVL---RDAQSKFFL--WVVKFNSLN 128
Cdd:cd10413   3 RTQPWFHGRISREESQRLIGQQGlvDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILpseEEGRLYFSMddGQTRFTDLL 82


                ....*..
gi 23344846 129 ELVEYHR 135
Cdd:cd10413  83 QLVEFHQ 89

Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. The Tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: Tensin1, Tensin2 (TENC1, C1-TEN), Tensin3 and Tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of Tensin2 and Tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein. PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway. Because of their PTEN-like domains, the Tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only Tensin2 and Tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198181 [Multi-domain] Cd Length: 116 Bit Score: 45.88 E-value: 1.24e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKC---PDGVQHFKVLRDAQS 115
Cdd:cd09927   5 WYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVatpPPGVNPFEAKGDPES 63

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb14 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR) and weakly to the erbB2 receptor. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198277 Cd Length: 108 Bit Score: 45.69 E-value: 1.31e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKH--EGAFLIRISESSPGDFSLSVKCPDGVQHFKVLR-DAQSKFFLWV----VKFNSLNELVE 132
Cdd:cd10414   7 WFHHKISRDEAQRLIIQQGlvDGVFLVRDSQSNPRTFVLSMSHGQKIKHFQIIPvEDDGELFHTLddghTRFTDLIQLVE 86


                ...
gi 23344846 133 YHR 135
Cdd:cd10414  87 FYQ 89

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 44.05 E-value: 1.39e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12073   3 AVALYDYQGEGDDEISFDPQETITDIEMVDEG-WWKGTCHGHRGLFPANYVEL 54

Src homology 3 domain of Lck Protein Tyrosine Kinase; Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212938 [Multi-domain] Cd Length: 54 Bit Score: 44.04 E-value: 1.49e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAE--LDGKEGLIPSNYIEM 55
Cdd:cd12005   3 VALYSYEPSHDGDLGFEKGEKLRIL--EQSGEWWKAQslTTGQEGFIPFNFVAK 54

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called RelA-associated inhibitor (RAI), is an oncoprotein that inhibits the apoptotic transactivation potential of p53. It is upregulated in human breast cancers expressing wild-type p53, in acute leukemias regardless of the p53 mutation status, as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212885 [Multi-domain] Cd Length: 56 Bit Score: 43.76 E-value: 1.54e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846   8 DFSATADDELSFRKTQILKILNME-DDSNWYRAELDGKEGLIPSNY 52
Cdd:cd11952   8 DYSAEFPDELSFKEGDMVTVLRKDgEGTDWWWASLCGREGYVPRNY 53

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 43.99 E-value: 1.57e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMED----DSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12059   4 AVFDYEASAEDELTLRRGDRVEVLSKDSavsgDEGWWTGKINDRVGIFPSNYVTS 58

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212868 [Multi-domain] Cd Length: 58 Bit Score: 43.84 E-value: 1.60e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYV 206
Cdd:cd11935   4 RAMYDYSAQDEDEVSFRDGDYIVNVQPIDEGWMYGTVqrTGRTGMLPANYI 54

Third N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212730 Cd Length: 51 Bit Score: 43.50 E-value: 1.66e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYI 53
Cdd:cd11796   2 ARVLQDLSAQLDEELDLREGDVVTITGILDK-GWFRGELNGRRGIFPEGFV 51

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 43.80 E-value: 1.67e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   5 AKHDFSATADD-ELSFRKTQILKILN----MEDDSNWYRAEL-DGKEGLIPSNYIE 54
Cdd:cd11771   4 ALYDFTPENPEmELSLKKGDIVAVLSktdpLGRDSEWWKGRTrDGRIGWFPSNYVE 59

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212792 [Multi-domain] Cd Length: 55 Bit Score: 43.91 E-value: 1.69e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWW----NGEigNRKGIFPATYVTP 208
Cdd:cd11858   4 ALYDFAGSVANELSLKKDDIVYIVQKEDNGWWlakkLDE--SKEGWVPAAYLEE 55

Third Src Homology 3 domain of SH3 domain containing ring finger 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212859 [Multi-domain] Cd Length: 55 Bit Score: 43.80 E-value: 1.83e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYVTP 208
Cdd:cd11926   4 AIYPYTPRKEDELELRKGEMFLVFERCQDGWFKGTSmhTSKIGVFPGNYVAP 55

Src Homology 3 domain of Bruton's tyrosine kinase; BTK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212839 [Multi-domain] Cd Length: 55 Bit Score: 43.66 E-value: 1.85e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 155 MLVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYVT 207
Cdd:cd11906   1 KKVVALYDYTPMNAQDLQLRKGEEYVILEESNLPWWRARDKNgREGYIPSNYVT 54

Third Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212946 Cd Length: 61 Bit Score: 43.91 E-value: 1.87e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 23344846  13 ADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12013  19 AEVELSFRAGDIITVFGEMDEDGFYYGELNGQRGLVPSNFLE 60

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212902 Cd Length: 55 Bit Score: 43.67 E-value: 2.05e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNR-KGIFPATYV 206
Cdd:cd11969   2 VKALYDYRAKRSDELSFCKGALIHNVSKETGGWWKGDYGGKvQHYFPSNYV 52

Fourth N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP bind the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212731 Cd Length: 50 Bit Score: 43.57 E-value: 2.10e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFP 202
Cdd:cd11797   4 ALYRFQALEPNELDFEVGDRIRIIATLEDGWLEGELKGRRGIFP 47

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212905 [Multi-domain] Cd Length: 61 Bit Score: 43.85 E-value: 2.15e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11972   5 VVAIYDYTKDKEDELSFQEGAIIYVIKKNDDGWYEGVMNGVTGLFPGNYV 54

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called SSU81 (Suppressor of SUA8-1 mutation), is a yeast membrane protein that regulates adaptation to high salt conditions by activating the HOG (high-osmolarity glycerol) pathway. High salt concentrations lead to the localization to the membrane of the MAPKK Pbs2, which is then activated by the MAPKK Ste11 and in turn, activates the MAPK Hog1. Pbs2 is localized to the membrane though the interaction of its PxxP motif with the SH3 domain of Sho1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212789 [Multi-domain] Cd Length: 55 Bit Score: 43.56 E-value: 2.17e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   3 AIAKHDFSATADD--ELSFRKTQILKILNMEddSNWYRAEL-DGKEGLIPSNYIEM 55
Cdd:cd11855   2 ARALYPYDASPDDpnELSFEKGEILEVSDTS--GKWWQARKsNGETGICPSNYLQL 55

Third Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212837 [Multi-domain] Cd Length: 57 Bit Score: 43.48 E-value: 2.19e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNM-EDDSNWYRA-ELDGKEGLIPSNYI 53
Cdd:cd11904   5 ALYPFSSSNDEELNFEKGEVMDVIEKpENDPEWWKCrKANGQVGLVPKNYV 55

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212933 Cd Length: 57 Bit Score: 43.71 E-value: 2.19e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILKIL--NMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12000   1 LLARALYDNKADCSDELAFRRGDILTVLeqNVPGSEGWWKCLLHGRQGLAPANRLQL 57

First Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212811 [Multi-domain] Cd Length: 54 Bit Score: 43.43 E-value: 2.21e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAE--LDGKEGLIPSNY 52
Cdd:cd11878   4 ALYDYRAQTPGELSFSKGDFFHVIGEEDQGEWYEATnpVTGKRGLVPKSY 53

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212827 Cd Length: 56 Bit Score: 43.39 E-value: 2.23e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNME--DDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11894   4 ALYDYEGQTDDELSFPEGAIIRILNKEnqDDDGFWEGEFNGRIGVFPSVLVE 55

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212904 [Multi-domain] Cd Length: 59 Bit Score: 43.47 E-value: 2.37e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYIEMKNH 58
Cdd:cd11971   1 KVVAIYDYSKDKDDELSFMEGAIIYVIKKNDDG-WYEGVCNGVTGLFPGNYVESIMH 56

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 43.35 E-value: 2.46e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846   9 FSATADDELSFRKTQILKILNME-DDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12057   8 YEAQNEDELTIKEGDIVTLISKDcIDAGWWEGELNGRRGVFPDNFVKL 55

First Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212852 [Multi-domain] Cd Length: 55 Bit Score: 43.41 E-value: 2.47e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11919   2 PARAKFDFKAQTLKELPLQKGDIVYIYK-QIDQNWYEGEHHGRVGIFPRSYIEL 54

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212752 [Multi-domain] Cd Length: 50 Bit Score: 43.24 E-value: 2.57e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQIlkILNMED-DSNWYRAELDGKEGLIPSNY 52
Cdd:cd11818   1 KARALYDFTGENEDELSFKAGDI--ITELESiDEEWMSGELRGKSGIFPKNF 50

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212809 [Multi-domain] Cd Length: 58 Bit Score: 43.27 E-value: 2.64e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNME----DDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11876   4 ALFDYDARGEDELTLRRGQPVEVLSKDaavsGDEGWWTGKIGDKVGIFPSNYV 56

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212853 [Multi-domain] Cd Length: 55 Bit Score: 43.46 E-value: 2.67e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11920   3 ARAVYDFKAQTSKELSFKKGDTVYILR-KIDQNWYEGEHHGRVGIFPISYVE 53

Src homology 3 domains of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212785 Cd Length: 62 Bit Score: 43.46 E-value: 2.93e-06

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 23344846 156 LVQALYDFVPQE-------SGELDFRRGDVITV-TDRSDENWWNGEI-GNRKGIFPATYVTP 208
Cdd:cd11851   1 LMVALYDYNPETmspnddpEEELSFHAGDVVRVyGPMDEDGFYYGELeGGRKGLVPSNFVQE 62

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 43.07 E-value: 3.08e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDdSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12060   6 ARFNFKQTNEDELSVCKGDIIYVTRVEE-GGWWEGTLNGKTGWFPSNYVR 54

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212939 [Multi-domain] Cd Length: 56 Bit Score: 43.11 E-value: 3.09e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSNW-YRAELDGKEGLIPSNYI 53
Cdd:cd12006   4 VALYDYEARTEDDLSFHKGEKFQILNSSEGDWWeARSLTTGETGYIPSNYV 54

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198246 Cd Length: 103 Bit Score: 44.49 E-value: 3.11e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVlRDAQSKFFLWVV--------KFN 125
Cdd:cd10383   3 ELSQTGWYWGSMTVNEAKEKLQDAPEGTFLVRDSSHSDYLLTISVKTSAGPTNLRI-EYQDGKFRLDSIicvksklkQFD 81

                        90
                ....*....|....*...
gi 23344846 126 SLNELVEYHRTASVSRSQ 143
Cdd:cd10383  82 SVVHLIEYYVQMCKDKRT 99

Src homology 3 domain of Lyn Protein Tyrosine Kinase; Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212937 [Multi-domain] Cd Length: 56 Bit Score: 43.06 E-value: 3.12e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAE--LDGKEGLIPSNYIEMKN 57
Cdd:cd12004   3 VALYPYDGIHEDDLSFKKGEKLKVI--EEHGEWWKARslTTKKEGFIPSNYVAKVN 56

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212986 Cd Length: 56 Bit Score: 42.91 E-value: 3.20e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12053   1 EYIVEYDYDAVHEDELTIRVGEIIRNVKKLEEEGWLEGELNGRRGMFPDNFVK 53

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212934 Cd Length: 68 Bit Score: 43.49 E-value: 3.28e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 155 MLVQALYDFVPQESGELDFRRGDVITVTDRSDE---NWWNGEIGNRKGIFPA 203
Cdd:cd12001   3 VLAKALYDNVAESPDELSFRKGDIMTVLERDTQgldGWWLCSLHGRQGIVPG 54

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212991 [Multi-domain] Cd Length: 58 Bit Score: 43.01 E-value: 3.42e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNME----DDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd12058   4 ALYDYEASGEDELSLRRGDVVEVLSQDaavsGDDGWWAGKIRHRLGIFPANYV 56

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 42.71 E-value: 3.43e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   9 FSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11874   8 YTPQNEDELELKVGDTIEVLG-EVEEGWWEGKLNGKVGVFPSNFVKE 53

Third Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212946 Cd Length: 61 Bit Score: 43.14 E-value: 3.46e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESG-------ELDFRRGDVITVTDRSDEN-WWNGEIGNRKGIFPATYVTP 208
Cdd:cd12013   4 ALFDYDPRESSpnvdaevELSFRAGDIITVFGEMDEDgFYYGELNGQRGLVPSNFLEE 61

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212866 [Multi-domain] Cd Length: 58 Bit Score: 43.07 E-value: 3.47e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYV 206
Cdd:cd11933   4 FRAMYDYRAADDDEVSFKDGDTIVNVQTIDEGWMYGTVqrTGKTGMLPANYV 55

Src homology 3 domain of RUN and SH3 domain-containing proteins 1 and 2; RUSC1 and RUSC2, that were originally characterized in silico. They are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC2, also called Iporin, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212744 Cd Length: 50 Bit Score: 42.82 E-value: 3.61e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNY 52
Cdd:cd11810   1 VVRALCHHVATDSGQLSFRKGDILRVIARVDD-DWLLCTRGSTKGLVPLSY 50

Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212887 [Multi-domain] Cd Length: 57 Bit Score: 43.08 E-value: 3.80e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDS--NWYRAELDGKEGLIPSNYI 53
Cdd:cd11954   8 DYEAQNADELSFQEGDAITILRRKDDSetEWWWARLNDKEGYVPKNLL 55

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212932 [Multi-domain] Cd Length: 56 Bit Score: 43.00 E-value: 3.89e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD-GKEGLIPSNYIE 54
Cdd:cd11999   6 AVYDYTGQEPDELSFKAGEELLKVEDEDEQGWCKGVTDgGAVGLYPANYVE 56

Second Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212864 Cd Length: 55 Bit Score: 42.60 E-value: 4.43e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 158 QALYDF----VPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11931   3 KALYDFeikdKDQDKDCLTFTKDEILTVIRRVDENWAEGMLGDKIGIFPILYV 55

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 42.76 E-value: 4.48e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSN-WYRAELDGKEGLIPSNYI 53
Cdd:cd11841   1 EVTALYSFEGQQPCDLSFQAGDRITVLTRTDSQFdWWEGRLRGRVGIFPANYV 53

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 42.50 E-value: 4.53e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVT--DRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12056   5 KALFHYEGTNEDELDFKEGEIILIIskDTGEPGWWKGELNGKEGVFPDNFV 55

Second Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212708 [Multi-domain] Cd Length: 52 Bit Score: 42.45 E-value: 4.55e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENW-WNGEIGNRKGIFPATYV 206
Cdd:cd11774   2 AKALYDYDKQTEEELSFNEGDTLDVYDDSDSDWiLVGFNGTQFGFVPANYI 52

First Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212854 Cd Length: 55 Bit Score: 42.60 E-value: 4.75e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKIlNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11921   3 ARLKFDFQAQSPKELTLQKGDIVYI-HKEVDKNWLEGEHHGRVGIFPANYVEV 54

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212741 [Multi-domain] Cd Length: 57 Bit Score: 42.37 E-value: 4.93e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDE---NWWNGEIGNRKGIFPATY 205
Cdd:cd11807   3 VYALFDYEAENGDELSFREGDELTVLRKGDDdetEWWWARLNDKEGYVPRNL 54

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 42.70 E-value: 5.76e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVT-----DRSDENWWNG--EIGNRKGIFPATYVTP 208
Cdd:cd11790   5 VRATHDYTAEDTDELTFEKGDVILVIpfddpEEQDEGWLMGvkESTGCRGVFPENFTER 63

Src Homology 3 domain of Bruton's tyrosine kinase; BTK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212839 [Multi-domain] Cd Length: 55 Bit Score: 42.50 E-value: 5.85e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRA-ELDGKEGLIPSNYI 53
Cdd:cd11906   1 KKVVALYDYTPMNAQDLQLRKGEEYVILE-ESNLPWWRArDKNGREGYIPSNYV 53

Src Homology 3 domain of Small G protein Signaling Modulator 3; SGSM3 is also called Merlin-associated protein (MAP), RUN and SH3 domain-containing protein (RUSC3), RUN and TBC1 domain-containing protein 3 (RUTBC3), Rab GTPase-activating protein 5 (RabGAP5), or Rab GAP-like protein (RabGAPLP). It is expressed ubiquitously and functions as a regulator of small G protein RAP- and RAB-mediated neuronal signaling. It is involved in modulating NGF-mediated neurite outgrowth and differentiation. It also interacts with the tumor suppressor merlin and may play a role in the merlin-associated suppression of cell growth. SGSM3 contains TBC, SH3, and RUN domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212747 Cd Length: 53 Bit Score: 42.10 E-value: 6.08e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDSNWYrAELDGKEGLIPSNYIEM 55
Cdd:cd11813   7 DFERHDDDELGFRKNDIITIISQKDEHCWV-GELNGLRGWFPAKFVEL 53

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198261 Cd Length: 106 Bit Score: 43.78 E-value: 6.10e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  55 MKNHDWYYGRITRADAEKLLSNK-HEGAFLIRISeSSPGDFSLSVKCPD------GVQHFKVLRDAQSKfflWVVK---- 123
Cdd:cd10398   3 LEIYEWYHKNITRNQAERLLRQEsKEGAFIVRDS-RHLGSYTISVFTRArrsteaSIKHYQIKKNDSGQ---WYVAerhl 78

                        90
                ....*....|..
gi 23344846 124 FNSLNELVEYHR 135
Cdd:cd10398  79 FQSIPELIQYHQ 90

First Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The first SH3 domain of Nck proteins preferentially binds the PxxDY sequence, which is present in the CD3e cytoplasmic tail. This binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212699 [Multi-domain] Cd Length: 51 Bit Score: 42.02 E-value: 6.16e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILnmeDDS-NWYRAELD-GKEGLIPSNYI 53
Cdd:cd11765   2 VVAKYDYTAQGDQELSIKKNEKLTLL---DDSkHWWKVQNSsNQTGYVPSNYV 51

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 42.11 E-value: 6.87e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11812   3 VALYDYTANRSDELTIHRGDIIRVLYKDNDNWWFGSLVNGQQGYFPANYV 52

Src homology 3 domain of Slit-Robo GTPase Activating Proteins 1, 2, and 3; srGAP1, also called Rho GTPase-Activating Protein 13 (ARHGAP13), is a Cdc42- and RhoA-specific GAP and is expressed later in the development of central nervous system tissues. srGAP2 is expressed in zones of neuronal differentiation. It plays a role in the regeneration of neurons and axons. srGAP3, also called MEGAP (MEntal disorder associated GTPase-Activating Protein), is a Rho GAP with activity towards Rac1 and Cdc42. It impacts cell migration by regulating actin and microtubule cytoskeletal dynamics. The association between srGAP3 haploinsufficiency and mental retardation is under debate. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212888 [Multi-domain] Cd Length: 53 Bit Score: 41.85 E-value: 7.80e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYI 53
Cdd:cd11955   1 EAIAKFDYVGRSARELSFKKGASLLLYHRASD-DWWEGRHNGIDGLVPHQYI 51

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212895 [Multi-domain] Cd Length: 54 Bit Score: 41.70 E-value: 8.15e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11962   2 AVVLYDYEKDEDNEIELVEGEIVTNIEMVDEDWWMGTNSKGESGLFPSNYVEL 54

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 41.99 E-value: 8.19e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYI 53
Cdd:cd11806   1 EYVAIADFVATDDSQLSFESGDKLLVLRKPSV-DWWWAEHNGCCGYIPASHL 51

Src homology 3 domain of RUN and SH3 domain-containing protein 1; RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC proteins are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212891 [Multi-domain] Cd Length: 51 Bit Score: 41.74 E-value: 8.55e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESgELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11958   2 VRALCDHAGSES-QLSFRKGEELQVLGTVDEDWIRCRRGDREGLVPVGYTS 51

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212800 Cd Length: 53 Bit Score: 41.65 E-value: 8.63e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDE--NWWNGEIGNRKGIFPATYV 206
Cdd:cd11866   3 MGLWDCSGNEPDELSFKRGDLIYIISKEYDsfGWWVGELNGKVGLVPKDYL 53

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing proteins, also called TULA (T cell Ubiquitin LigAnd) family of proteins; UBASH3 or TULA proteins are also referred to as Suppressor of T cell receptor Signaling (STS) proteins. They contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. In some vertebrates, there are two TULA family proteins, called UBASH3A (also called TULA or STS-2) and UBASH3B (also called TULA-2 or STS-1), which show partly overlapping as well as distinct functions. UBASH3B is widely expressed while UBASH3A is only found in lymphoid cells. UBASH3A facilitates apoptosis induced in T cells through its interaction with the apoptosis-inducing factor AIF. UBASH3B is an active phosphatase while UBASH3A is not. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212725 [Multi-domain] Cd Length: 59 Bit Score: 41.90 E-value: 8.93e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVI----TVTDRSDENWWNGeIGNR---KGIFPATYVT 207
Cdd:cd11791   2 LRVLYPYTPQEEDELELVPGDYIyvspEELDSSSDGWVEG-TSWLtgcSGLLPENYTE 58

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212940 [Multi-domain] Cd Length: 58 Bit Score: 41.94 E-value: 9.43e-06

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAE--LDGKEGLIPSNYI 53
Cdd:cd12007   4 VALYDYEARTTEDLSFKKGERFQIIN-NTEGDWWEARsiATGKNGYIPSNYV 54

Third Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the third SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212950 Cd Length: 53 Bit Score: 41.67 E-value: 9.79e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   8 DFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12017   7 EFQATIQDGISFQKGQKVEVID-KNPSGWWYVKIDGKEGWAPSSYIE 52

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 41.53 E-value: 1.02e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   4 IAKHDFSATADDELSFRKTQIlkILNMED-DSNWY--RAELDGKEGLIPSNYIEM 55
Cdd:cd11789   3 RAMYDYAAADDDEVSFQEGDV--IINVEIiDDGWMegTVQRTGQSGMLPANYVEL 55

Src Homology 3 domain of Sorting nexin 18; SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. It binds FIP5 and is required for apical lumen formation. It may also play a role in axonal elongation. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX18 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212830 [Multi-domain] Cd Length: 55 Bit Score: 41.52 E-value: 1.08e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSD-ENWWNGeIGNR--KGIFPATYV 206
Cdd:cd11897   3 RALYDFRSENPGEISLREHEVLSLCSEQDiEGWLEG-VNSRgdRGLFPASYV 53

Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198279 Cd Length: 102 Bit Score: 42.72 E-value: 1.12e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPgDFSLSVKCPDGVQHFKV--LRDAQ 114
Cdd:cd10416   9 WFHGFITRREAERLLEPKPQGCYLVRFSESAV-TFVLTYRSRTCCRHFLLaqLRDGR 64

Second Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212749 [Multi-domain] Cd Length: 52 Bit Score: 41.40 E-value: 1.21e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11815   2 AVVLHDFPAEHSDDLSLNSGEIVYLLE-KIDTEWYRGKCKNTTGIFPANHVK 52

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212893 [Multi-domain] Cd Length: 54 Bit Score: 41.23 E-value: 1.23e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11960   2 ARALYDYQAADDTEISFDPGDIITDIEQIDEGWWRGTGPDGTYGLFPANYVEL 54

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198247 Cd Length: 101 Bit Score: 42.80 E-value: 1.24e-05

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSkFFL 119
Cdd:cd10384  12 FYWSTVSGKEANLLLSAEPAGTFLIRDSSDQRHFFTLSVKTESGTKNLRIQCEGGS-FSL 70

Second Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212855 [Multi-domain] Cd Length: 58 Bit Score: 41.52 E-value: 1.45e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDG--KEGLIPSNYIEM 55
Cdd:cd11922   2 EAIAKFNFNGDTQVEMSFRKGERITLLRQVDE-NWYEGRIPGtsRQGIFPITYVDV 56

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212904 [Multi-domain] Cd Length: 59 Bit Score: 41.16 E-value: 1.50e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11971   2 VVAIYDYSKDKDDELSFMEGAIIYVIKKNDDGWYEGVCNGVTGLFPGNYV 51

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212702 [Multi-domain] Cd Length: 54 Bit Score: 41.10 E-value: 1.60e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmeDDSN--WYRA-ELDGKEGLIPSNYIE 54
Cdd:cd11768   3 VALYDFQPIEPGDLPLEKGEEYVVL---DDSNehWWRArDKNGNEGYIPSNYVT 53

Src homology 2 (SH2) domain found in cytokine-inducible SH2-containing protein (CIS); CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of the CIS gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Suppressor of cytokine signalling (SOCS) was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198285 Cd Length: 88 Bit Score: 42.05 E-value: 1.70e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVK 99
Cdd:cd10718   6 WYWGSITASEAHQALQKAPEGTFLVRDSSHPSYMLTLSVK 45

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212778 Cd Length: 56 Bit Score: 41.18 E-value: 1.70e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKIL--NMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11844   2 ARALYDNVAESPDELAFRRGDILTVLeqNTAGLEGWWLCSLRGRQGIAPGNRLKL 56

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 41.15 E-value: 1.77e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNG--EIGNRKGIFPATYVTP 208
Cdd:cd11789   4 AMYDYAAADDDEVSFQEGDVIINVEIIDDGWMEGtvQRTGQSGMLPANYVEL 55

Src Homology 3 domain of Membrane Protein, Palmitoylated (or MAGUK p55 subfamily member) proteins; The MPP/p55 subfamily of MAGUK (membrane-associated guanylate kinase) proteins includes at least eight vertebrate members (MPP1-7 and CASK), four Drosophila proteins (Stardust, Varicose, CASK and Skiff), and other similar proteins; they all contain one each of the core of three domains characteristic of MAGUK proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, most members except for MPP1 contain N-terminal L27 domains and some also contain a Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. CASK has an additional calmodulin-dependent kinase (CaMK)-like domain at the N-terminus. Members of this subfamily are scaffolding proteins that play important roles in regulating and establishing cell polarity, cell adhesion, and synaptic targeting and transmission, among others. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212796 Cd Length: 61 Bit Score: 41.03 E-value: 1.78e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVP--------QESGeLDFRRGDVITVTDRSDENWWN----GEIGNRKGIFPA 203
Cdd:cd11862   2 VRALFDYDPeedplipcKEAG-LSFKKGDILQIVNQDDPNWWQarkvGDPNGRAGLIPS 59

Src Homology 3 (SH3) domain of Apoptosis Stimulating of p53 protein 2; ASPP2 is the full length form of the previously-identified tumor supressor, p53-binding protein 2 (p53BP2). ASPP2 activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). It plays a central role in regulating apoptosis and cell growth; ASPP2-deficient mice show postnatal death. Downregulated expression of ASPP2 is frequently found in breast tumors, lung cancer, and diffuse large B-cell lymphoma where it is correlated with a poor clinical outcome. ASPP2 contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP2 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212886 [Multi-domain] Cd Length: 57 Bit Score: 41.09 E-value: 1.88e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846   8 DFSATADDELSFRKTQILKILNMED--DSNWYRAELDGKEGLIPSN 51
Cdd:cd11953   8 DYEGESDDELSFKEGDCMTILRREDedETEWWWARLNDKEGYVPRN 53

Src Homology 3 domain of Membrane Protein, Palmitoylated 7 (or MAGUK p55 subfamily member 7); MPP7 is a scaffolding protein that binds to DLG1 and promotes tight junction formation and epithelial cell polarity. Mutations in the MPP7 gene may be associated with the pathogenesis of diabetes and extreme bone mineral density. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212966 Cd Length: 61 Bit Score: 41.16 E-value: 1.92e-05

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 23344846 156 LVQALYDFVPQE-------SGELDFRRGDVITVTDRSDENWWN----GEIGNRKGIFPATY 205
Cdd:cd12033   1 FIKALFDYNPNEdkaipckEAGLSFKKGDILQIMSQDDATWWQakheGDANPRAGLIPSKH 61

N-terminal (or first) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. The N-terminal SH3 domain increases the affinity of p67phox for the oxidase complex. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212804 Cd Length: 54 Bit Score: 40.66 E-value: 2.09e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 160 LYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd11871   5 LYEFVPETKEELQVLPGNIVFVLKKGTDNWATVVFNGKKGLVPCNFLEP 53

Src Homology 3 domain of Cdc42-Interacting Protein 4; This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. It functions downstream of Cdc42 in PDGF-dependent actin reorganization and cell migration, and also regulates the activity of PDGFRbeta. It uses Src as a substrate in regulating the invasiveness of breast tumor cells. CIP4 may also play a role in the pathogenesis of Huntington's disease. Members of this subfamily typically contain an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of CIP4 associates with Gapex-5, a Rab31 GEF. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212844 [Multi-domain] Cd Length: 55 Bit Score: 40.71 E-value: 2.18e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRA-ELDGKEGLIPSNYIEM 55
Cdd:cd11911   2 CTALYDFDGTSEGTLSMEEGEILLVLEEDGGDGWTRVrKNNGDEGYVPTSYIEV 55

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 2; GRAF2, also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA. It regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle, and is involved in alpha-catenin recruitment at cell-cell junctions. GRAF2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212998 [Multi-domain] Cd Length: 54 Bit Score: 40.74 E-value: 2.25e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12065   1 KAKAVYPCEAEHSSELSFEVGAIFEDVTLSREPGWLEGTLNGKRGLIPENYVEI 54

Src Homology 3 domain of CSK homologous kinase; CHK is also referred to as megakaryocyte-associated tyrosine kinase (Matk). It inhibits Src kinases using a noncatalytic mechanism by simply binding to them. As a negative regulator of Src kinases, Chk may play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. To inhibit Src kinases that are anchored to the plasma membrane, CHK is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. CHK also plays a role in neural differentiation in a manner independent of Src by enhancing MAPK activation via Ras-mediated signaling. It is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212745 Cd Length: 59 Bit Score: 40.95 E-value: 2.29e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD--GKEGLIPS 50
Cdd:cd11811   3 QCVTKKDHTKPKPGELAFHKGDIVTIVETCERKGWYRARHNtsGEEGLVAA 53

Src homology 3 domain of RUN and SH3 domain-containing protein 1; RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC proteins are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212891 [Multi-domain] Cd Length: 51 Bit Score: 40.59 E-value: 2.32e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 23344846  11 ATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNY 52
Cdd:cd11958   9 AGSESQLSFRKGEELQVLGTVDE-DWIRCRRGDREGLVPVGY 49

Third Src Homology 3 domain of Nck adaptor proteins; This group contains the third SH3 domain of Nck, the first SH3 domain of Caenorhabditis elegans Ced-2 (Cell death abnormality protein 2), and similar domains. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. Ced-2 is a cell corpse engulfment protein that interacts with Ced-5 in a pathway that regulates the activation of Ced-10, a Rac small GTPase.

Pssm-ID: 212701 [Multi-domain] Cd Length: 56 Bit Score: 40.76 E-value: 2.51e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDR--SDENWW-----NGEIgnrkGIFPATYVT 207
Cdd:cd11767   2 VVALYPFTGENDEELSFEKGERLEIIEKpeDDPDWWkarnaLGTT----GLVPRNYVE 55

Src Homology 3 domain of eumetazoan Peroxisomal biogenesis factor 13; PEX13 is a peroxin and is required for protein import into the peroxisomal matrix and membrane. It is an integral membrane protein that is essential for the localization of PEX14 and the import of proteins containing the peroxisome matrix targeting signals, PTS1 and PTS2. Mutations of the PEX13 gene in humans lead to a wide range of peroxisome biogenesis disorders (PBDs), the most severe of which is known as Zellweger syndrome (ZS), a severe multisystem disorder characterized by hypotonia, psychomotor retardation, and neuronal migration defects. PEX13 contains two transmembrane regions and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212798 Cd Length: 58 Bit Score: 40.69 E-value: 2.51e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDEN----WWNGEIGNRK-GIFPATYVT 207
Cdd:cd11864   3 RAEYDFVAESEDELSFRAGDKLRLAPKELQPrvrgWLLATVDGQKiGLVPANYVK 57

Src Homology 3 (SH3) domain of Apoptosis Stimulating of p53 protein 2; ASPP2 is the full length form of the previously-identified tumor supressor, p53-binding protein 2 (p53BP2). ASPP2 activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). It plays a central role in regulating apoptosis and cell growth; ASPP2-deficient mice show postnatal death. Downregulated expression of ASPP2 is frequently found in breast tumors, lung cancer, and diffuse large B-cell lymphoma where it is correlated with a poor clinical outcome. ASPP2 contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP2 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212886 [Multi-domain] Cd Length: 57 Bit Score: 40.71 E-value: 2.54e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDEN---WWNGEIGNRKGIFP 202
Cdd:cd11953   2 VVYALWDYEGESDDELSFKEGDCMTILRREDEDeteWWWARLNDKEGYVP 51

First Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the first SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213007 [Multi-domain] Cd Length: 53 Bit Score: 40.47 E-value: 2.54e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 23344846 166 QESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12074  11 QENSEISLQAGEVVDVIEKNESGWWFVSTAEEQGWVPATYL 51

First Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212811 [Multi-domain] Cd Length: 54 Bit Score: 40.35 E-value: 2.69e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWW---NGEIGNRKGIFPATY 205
Cdd:cd11878   2 IRALYDYRAQTPGELSFSKGDFFHVIGEEDQGEWyeaTNPVTGKRGLVPKSY 53

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198250 Cd Length: 100 Bit Score: 41.75 E-value: 2.75e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  60 WYYGRITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVK 99
Cdd:cd10387  12 WYWGPITRWEAEGKLANVPDGSFLVRDSSDDRYLLSLSFR 51

First or N-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212954 [Multi-domain] Cd Length: 53 Bit Score: 40.32 E-value: 2.91e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12021   3 RAIADYEKSSKSEMALKTGDVVEVVEKSENGWWFCQLKAKRGWVPASYLEP 53

Second Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212857 Cd Length: 56 Bit Score: 40.33 E-value: 2.92e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDG--KEGLIPSNYIEM 55
Cdd:cd11924   2 EAVAQYTFKGDLEVELSFRKGEHICLIR-KVNENWYEGRITGtgRQGIFPASYVQV 56

Third Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. The third SH3 domain of Sla1p can bind ubiquitin while retaining the ability to bind proline-rich ligands; monoubiquitination of target proteins signals internalization and sorting through the endocytic pathway. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212709 [Multi-domain] Cd Length: 57 Bit Score: 40.38 E-value: 2.94e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 158 QALYDFVPQESGELDFRRGDVIT-VTDRSDENWWNGEI--GNRKGIFPATYVTP 208
Cdd:cd11775   4 KVLYDFDAQSDDELTVKEGDVVYiLDDKKSKDWWMVENvsTGKEGVVPASYIEI 57

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 40.43 E-value: 3.05e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAEL-DGKEGLIPSNYIEM 55
Cdd:cd11837   2 ATALYPWRAKKENHLSFAKGDIITVL--EQQEMWWFGELeGGEEGWFPKSYVKE 53

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212734 [Multi-domain] Cd Length: 57 Bit Score: 40.43 E-value: 3.07e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDEN----WWNGEIGNRKGIFPATYVTP 208
Cdd:cd11800   4 ALYTFEARSPGELSVTEGQVVTVLEKHDLKgnpeWWLVEDRGKQGYVPSNYLAK 57

Src Homology 3 domain of Tec (Tyrosine kinase expressed in hepatocellular carcinoma); Tec is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212838 [Multi-domain] Cd Length: 56 Bit Score: 40.18 E-value: 3.08e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRA-ELDGKEGLIPSNYIEMK 56
Cdd:cd11905   3 VVAMYDFQPTEPHDLRLETGEEYVILE-KNDVHWWKArDKYGKEGYIPSNYVTGK 56

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 40.39 E-value: 3.19e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   5 AKHDFSATADDELSFRKTQIlkILNME-DDSNWYRAELDGK-EGLIPSNYIE 54
Cdd:cd11825   4 ALYDYRAQRPDELSFCKHAI--ITNVEkEDGGWWRGDYGGKkQKWFPANYVE 53

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called RelA-associated inhibitor (RAI), is an oncoprotein that inhibits the apoptotic transactivation potential of p53. It is upregulated in human breast cancers expressing wild-type p53, in acute leukemias regardless of the p53 mutation status, as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212885 [Multi-domain] Cd Length: 56 Bit Score: 40.30 E-value: 3.27e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDE--NWWNGEIGNRKGIFPATY 205
Cdd:cd11952   3 VYALWDYSAEFPDELSFKEGDMVTVLRKDGEgtDWWWASLCGREGYVPRNY 53

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 40.26 E-value: 3.35e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGNRKGIFPATY 205
Cdd:cd11845   4 ALYDYEARTDDDLSFKKGDRLQILDDSDGDWWLARhlSTGKEGYIPSNY 52

Src Homology 3 domain of Membrane Protein, Palmitoylated 5 (or MAGUK p55 subfamily member 5); MPP5, also called PALS1 (Protein associated with Lin7) or Nagie oko protein in zebrafish or Stardust in Drosophila, is a scaffolding protein which associates with Crumbs homolog 1 (CRB1), CRB2, or CRB3 through its PDZ domain and with PALS1-associated tight junction protein (PATJ) or multi-PDZ domain protein 1 (MUPP1) through its L27 domain. The resulting tri-protein complexes are core proteins of the Crumb complex, which localizes at tight junctions or subapical regions, and is involved in the maintenance of apical-basal polarity in epithelial cells and the morphogenesis and function of photoreceptor cells. MPP5 is critical for the proper stratification of the retina and is also expressed in T lymphocytes where it is important for TCR-mediated activation of NFkB. Drosophila Stardust exists in several isoforms, some of which show opposing functions in photoreceptor cells, which suggests that the relative ratio of different Crumbs complexes regulates photoreceptor homeostasis. MPP5 contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212969 Cd Length: 63 Bit Score: 40.47 E-value: 3.38e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  17 LSFRKTQILKILNMEDDsNWYRAELDGKE------GLIPS 50
Cdd:cd12036  23 LSFQKGDILHVISQEDP-NWWQAYREGEEdnqslaGLIPS 61

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212910 [Multi-domain] Cd Length: 58 Bit Score: 40.38 E-value: 3.50e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILN-MEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11977   3 AVARYNFAARDMRELSLREGDVVRIYSrIGGDQGWWKGETNGRIGWFPSTYVE 55

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX[VI], which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198263 Cd Length: 103 Bit Score: 41.37 E-value: 3.68e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846  61 YYGRITRADAEKLLSNK-HEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRD 112
Cdd:cd10400   6 YHGKISRETGEKLLLAAgLDGSYLLRDSESVPGVYCLCVLYKGYVYTYRVSQT 58

Src homology 3 domain of Endophilin-B; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain two endophilin-B isoforms. Endophilin-B proteins are cytoplasmic proteins expressed mainly in the heart, placenta, and skeletal muscle. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212736 [Multi-domain] Cd Length: 52 Bit Score: 39.96 E-value: 3.85e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 159 ALYDFVPQESGELDFRRGDVITV--TDRSDENWWNGEIGNRKGIFPATY 205
Cdd:cd11802   4 VLYDYDAEDSTELSLLADEVITVyeLPGMDEDYMMGERGSQRGKVPVAY 52

Src Homology 3 domain of Membrane Protein, Palmitoylated 7 (or MAGUK p55 subfamily member 7); MPP7 is a scaffolding protein that binds to DLG1 and promotes tight junction formation and epithelial cell polarity. Mutations in the MPP7 gene may be associated with the pathogenesis of diabetes and extreme bone mineral density. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212966 Cd Length: 61 Bit Score: 40.00 E-value: 4.55e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  17 LSFRKTQILKILNmEDDSNWYRAELDG----KEGLIPSNY 52
Cdd:cd12033  23 LSFKKGDILQIMS-QDDATWWQAKHEGdanpRAGLIPSKH 61

First Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The first SH3 domain of Nck2 binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212832 [Multi-domain] Cd Length: 58 Bit Score: 40.11 E-value: 4.58e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAE-LDGKEGLIPSNYIEMK 56
Cdd:cd11899   7 IAKWDYTAQQDQELDIKKNERLWLL--DDSKTWWRVRnAANRTGYVPSNYVERK 58

Third Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212718 Cd Length: 55 Bit Score: 39.76 E-value: 4.66e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGNRKGIFPATYVTP 208
Cdd:cd11784   4 ALHSYSAHRPEELELQKGEGVRVLGKFQEGWLRGLslVTGRVGIFPSNYVSP 55

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called SSU81 (Suppressor of SUA8-1 mutation), is a yeast membrane protein that regulates adaptation to high salt conditions by activating the HOG (high-osmolarity glycerol) pathway. High salt concentrations lead to the localization to the membrane of the MAPKK Pbs2, which is then activated by the MAPKK Ste11 and in turn, activates the MAPK Hog1. Pbs2 is localized to the membrane though the interaction of its PxxP motif with the SH3 domain of Sho1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212789 [Multi-domain] Cd Length: 55 Bit Score: 39.71 E-value: 4.68e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 157 VQALYDFV--PQESGELDFRRGDVITVTDRSDeNWWNGEIGN-RKGIFPATYV 206
Cdd:cd11855   2 ARALYPYDasPDDPNELSFEKGEILEVSDTSG-KWWQARKSNgETGICPSNYL 53

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212867 [Multi-domain] Cd Length: 59 Bit Score: 39.98 E-value: 4.94e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRK-TQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11934   7 AVYDYNAADEDEVSFQDgDTIVNVQQIDDGWMYGTVERTGDTGMLPANYVE 57

First Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212861 Cd Length: 54 Bit Score: 39.52 E-value: 5.52e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  16 ELSFRKTQILkILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11928  16 DLKFNKGDII-ILRRKVDENWYHGELNGCHGFLPASYIQC 54

C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Syk. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198264 Cd Length: 99 Bit Score: 40.64 E-value: 5.70e-05

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846  60 WYYGRITRADAEKLLSN--KHEGAFLIRISESSpGDFSLSVKCPDGVQHFKVLRDAQSKFFLWV-VKFNSLNELVEYH 134
Cdd:cd10401   5 WFHGKISREESEQILLIgsKTNGKFLIRERDNN-GSYALCLLHDGKVLHYRIDKDKTGKLSIPDgKKFDTLWQLVEHY 81

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 39.63 E-value: 5.77e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQilKILNMEDDSN-WYRAELDGKEGLIPSNYI 53
Cdd:cd11901   2 LPAYVKFNYTAEREDELSLVKGT--KVIVMEKCSDgWWRGSYNGQVGWFPSNYV 53

Src homology 3 domain of Blk Protein Tyrosine Kinase; Blk is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. It is expressed specifically in B-cells and is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212942 [Multi-domain] Cd Length: 54 Bit Score: 39.41 E-value: 6.37e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTdRSDENWWNGE--IGNRKGIFPATYVTP 208
Cdd:cd12009   2 VIAQYDFVPSNERDLQLKKGEKLQVL-KSDGEWWLAKslTTGKEGYIPSNYVAR 54

Third Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212836 [Multi-domain] Cd Length: 59 Bit Score: 39.66 E-value: 6.46e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   9 FSATADDELSFRKTQILKILNM-EDDSNWYRAE-LDGKEGLIPSNYI 53
Cdd:cd11903   9 FSSVTEEELNFEKGETMEVIEKpENDPEWWKCKnSRGQVGLVPKNYV 55

Src Homology 3 domain of Membrane Protein, Palmitoylated (or MAGUK p55 subfamily member) proteins; The MPP/p55 subfamily of MAGUK (membrane-associated guanylate kinase) proteins includes at least eight vertebrate members (MPP1-7 and CASK), four Drosophila proteins (Stardust, Varicose, CASK and Skiff), and other similar proteins; they all contain one each of the core of three domains characteristic of MAGUK proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, most members except for MPP1 contain N-terminal L27 domains and some also contain a Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. CASK has an additional calmodulin-dependent kinase (CaMK)-like domain at the N-terminus. Members of this subfamily are scaffolding proteins that play important roles in regulating and establishing cell polarity, cell adhesion, and synaptic targeting and transmission, among others. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212796 Cd Length: 61 Bit Score: 39.49 E-value: 6.58e-05

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 23344846  17 LSFRKTQILKILNMEDDsNWYRA----ELDGKEGLIPS 50
Cdd:cd11862  23 LSFKKGDILQIVNQDDP-NWWQArkvgDPNGRAGLIPS 59

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 2; SKAP2, also called SKAP55-Related (SKAP55R) or SKAP55 homolog (SKAP-HOM or SKAP55-HOM), is an immune cell-specific adaptor protein that plays an important role in adhesion and migration of B-cells and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), YopH, SHPS1, and HPK1. SKAP2 has also been identified as a substrate for lymphoid-specific tyrosine phosphatase (Lyp), which has been implicated in a wide variety of autoimmune diseases. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. Like SKAP1, SKAP2 is expected to bind primarily to a proline-rich region of ADAP through its SH3 domain; its degradation may be regulated by ADAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212978 Cd Length: 53 Bit Score: 39.50 E-value: 6.62e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDE--NWWNGEIGNRKGIFPATYV 206
Cdd:cd12045   3 QGLWDCTGDQPDELSFKRGDTIYILSKEYNrfGWWVGEMKGTIGLVPKAYI 53

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212940 [Multi-domain] Cd Length: 58 Bit Score: 39.63 E-value: 6.75e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN--RKGIFPATYVTP 208
Cdd:cd12007   5 ALYDYEARTTEDLSFKKGERFQIINNTEGDWWEARSIAtgKNGYIPSNYVAP 56

Second C-terminal Src homology 3 domain of Rho guanine nucleotide exchange factor 37; ARHGEF37 contains a RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. Its specific function is unknown. Its domain architecture is similar to the C-terminal half of DNMBP or Tuba, a cdc42-specific GEF that provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics, and plays an important role in regulating cell junction configuration. GEFs activate small GTPases by exchanging bound GDP for free GTP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212874 Cd Length: 57 Bit Score: 39.51 E-value: 6.84e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMED---DSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11941   1 QVVAAYPFTARSKHEVSLQAGQPVTVLEPHDkkgSPEWSLVEVNGQRGYVPSSYL 55

Src homology 3 domain of Slit-Robo GTPase Activating Proteins 1, 2, and 3; srGAP1, also called Rho GTPase-Activating Protein 13 (ARHGAP13), is a Cdc42- and RhoA-specific GAP and is expressed later in the development of central nervous system tissues. srGAP2 is expressed in zones of neuronal differentiation. It plays a role in the regeneration of neurons and axons. srGAP3, also called MEGAP (MEntal disorder associated GTPase-Activating Protein), is a Rho GAP with activity towards Rac1 and Cdc42. It impacts cell migration by regulating actin and microtubule cytoskeletal dynamics. The association between srGAP3 haploinsufficiency and mental retardation is under debate. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212888 [Multi-domain] Cd Length: 53 Bit Score: 39.16 E-value: 6.90e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11955   4 AKFDYVGRSARELSFKKGASLLLYHRASDDWWEGRHNGIDGLVPHQYI 51

Src Homology 3 domain of Interleukin-2-inducible T-cell Kinase; ITK (also known as Tsk or Emt) is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. ITK is expressed in T-cells and mast cells, and is important in their development and differentiation. Of the three Tec kinases expressed in T-cells, ITK plays the predominant role in T-cell receptor (TCR) signaling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization. It also plays a role in the downstream signaling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4. In addition, ITK is crucial for the development of T-helper(Th)2 effector responses. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212841 [Multi-domain] Cd Length: 56 Bit Score: 39.23 E-value: 7.02e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGN-RKGIFPATYV 206
Cdd:cd11908   2 LVIALYDYQTNDPQELALRYNEEYHLLDSSEIHWWRVQDKNgHEGYVPSSYL 53

Src Homology 3 domain of Membrane Protein, Palmitoylated 3 (or MAGUK p55 subfamily member 3); MPP3 is a scaffolding protein that colocalizes with MPP5 and CRB1 at the subdpical region adjacent to adherens junctions and may function in photoreceptor polarity. It interacts with some nectins and regulates their trafficking and processing. Nectins are cell-cell adhesion proteins involved in the establishment apical-basal polarity at cell adhesion sites. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212972 Cd Length: 62 Bit Score: 39.56 E-value: 7.05e-05

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVP--------QESGeLDFRRGDVITVTDRSDENWWN----GEIGNRKGIFPAT 204
Cdd:cd12039   2 MRALFDYNPyedraipcQEAG-LPFKRRDILEVVSQDDPTWWQakrvGDTNLRAGLIPSK 60

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 39.59 E-value: 7.15e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   5 AKHDFSATADDELSFRKTQIlkILNME-DDSNWYRAELDGKEGL-IPSNYIE 54
Cdd:cd11970   8 ALFDYKAQREDELTFTKNAI--IQNVEkQEGGWWRGDYGGKKQLwFPSNYVE 57

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 39.24 E-value: 7.95e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAE--LDGKEGLIPSNYIE 54
Cdd:cd11793   1 QVQCVHAYTAQQPDELTLEEGDVVNVLRKMPDG-WYEGErlRDGERGWFPSSYTE 54

First N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212728 Cd Length: 51 Bit Score: 39.04 E-value: 8.17e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11794   2 VRAIFDFCPSVSEELPLFAGDVIEVLKVVDEFWLLGTKEGVTGQFPSSFV 51

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212868 [Multi-domain] Cd Length: 58 Bit Score: 39.22 E-value: 8.60e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWY-RAELDGKEGLIPSNYIEMKN 57
Cdd:cd11935   5 AMYDYSAQDEDEVSFRDGDYIVNVQPIDEGWMYgTVQRTGRTGMLPANYIEFVN 58

Src homology 3 domain of the Protein Tyrosine Kinase, Abelson kinase; Abl (or c-Abl) is a ubiquitously-expressed cytoplasmic (or nonreceptor) PTK that contains SH3, SH2, and tyr kinase domains in its N-terminal region, as well as nuclear localization motifs, a putative DNA-binding domain, and F- and G-actin binding domains in its C-terminal tail. It also contains a short autoinhibitory cap region in its N-terminus. Abl function depends on its subcellular localization. In the cytoplasm, Abl plays a role in cell proliferation and survival. In response to DNA damage or oxidative stress, Abl is transported to the nucleus where it induces apoptosis. In chronic myelogenous leukemia (CML) patients, an aberrant translocation results in the replacement of the first exon of Abl with the BCR (breakpoint cluster region) gene. The resulting BCR-Abl fusion protein is constitutively active and associates into tetramers, resulting in a hyperactive kinase sending a continuous signal. This leads to uncontrolled proliferation, morphological transformation and anti-apoptotic effects. BCR-Abl is the target of selective inhibitors, such as imatinib (Gleevec), used in the treatment of CML. Abl2, also known as ARG (Abelson-related gene), is thought to play a cooperative role with Abl in the proper development of the nervous system. The Tel-ARG fusion protein, resulting from reciprocal translocation between chromosomes 1 and 12, is associated with acute myeloid leukemia (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212784 Cd Length: 56 Bit Score: 38.93 E-value: 8.61e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD--GKEGLIPSNYI 53
Cdd:cd11850   3 VALYDFVASGENQLSIKKGEQLRVLGYNKNGEWCEAESKstGGQGWVPSNYI 54

First Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The first SH3 domain of Nck1 binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212833 [Multi-domain] Cd Length: 59 Bit Score: 39.32 E-value: 9.05e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDSNWYRAE-LDGKEGLIPSNYIEMKN 57
Cdd:cd11900   6 VAKFDYVAQQDQELDIKKNERLWLL--DDSKSWWRVRnAMNKTGFVPSNYVERKN 58

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also called Rho GTPase activating protein 26 (ARHGAP26), Oligophrenin-1-like (OPHN1L) or GRAF1, is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. It is essential for the major clathrin-independent endocytic pathway mediated by pleiomorphic membranes. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212997 Cd Length: 56 Bit Score: 38.94 E-value: 9.40e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12064   2 KAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVE 54

Src Homology 3 domain of Tec (Tyrosine kinase expressed in hepatocellular carcinoma); Tec is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212838 [Multi-domain] Cd Length: 56 Bit Score: 39.03 E-value: 9.56e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNG--EIGNrKGIFPATYVT 207
Cdd:cd11905   2 IVVAMYDFQPTEPHDLRLETGEEYVILEKNDVHWWKArdKYGK-EGYIPSNYVT 54

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 38.86 E-value: 9.61e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846 161 YDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11901   8 FNYTAEREDELSLVKGTKVIVMEKCSDGWWRGSYNGQVGWFPSNYVT 54

C-terminal (Fourth) Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the fourth SH3 domain, located at the C-terminus of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212719 Cd Length: 55 Bit Score: 38.99 E-value: 1.00e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 165 PQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYVTP 208
Cdd:cd11785  10 PQSEAELELKEGDIVFVHKKREDGWFKGTLqrTGKTGLFPGSFVES 55

N-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also have roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212880 [Multi-domain] Cd Length: 52 Bit Score: 38.62 E-value: 1.11e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDrSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11947   3 RGKFDFTASGEDELSFKKGDVLKILS-SDDIWFKAELNGEEGYVPKNFV 50

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212934 Cd Length: 68 Bit Score: 39.25 E-value: 1.22e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDD--SNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12001   5 AKALYDNVAESPDELSFRKGDIMTVLERDTQglDGWWLCSLHGRQGIVPGNRLKI 59

Src homology 3 domain of Endophilin-B2; Endophilin-B2, also called SH3GLB2 (SH3-domain GRB2-like endophilin B2), is a cytoplasmic protein that interacts with the apoptosis inducer Bax. It is overexpressed in prostate cancer metastasis and has been identified as a cancer antigen with potential utility in immunotherapy. Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. Endophilin-B2 forms homo- and heterodimers (with endophilin-B1) through its BAR domain. The related protein endophilin-B1 interacts with amphiphysin 1 and dynamin 1 through its SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212877 Cd Length: 55 Bit Score: 38.82 E-value: 1.22e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYV 206
Cdd:cd11944   3 RVLYDYEAADSSELALLADELITVYSLPgmDPDWLIGERGNQKGKVPVTYL 53

Src homology 3 domain of Src-Like Adaptor Protein 2; SLAP2 plays a role in c-Cbl-dependent regulation of CSF1R, a tyrosine kinase important for myeloid cell growth and differentiation. It has been shown to interact with CSF1R, c-Cbl, LAT, CD247, and Zap70. SLAPs are adaptor proteins with limited similarity to Src family tyrosine kinases. They contain an N-terminal SH3 domain followed by an SH2 domain, and a unique C-terminal sequence. They function in regulating the signaling, ubiquitination, and trafficking of T-cell receptor (TCR) and B-cell receptor (BCR) components. The SH3 domain of SLAP forms a complex with v-Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212944 Cd Length: 55 Bit Score: 38.57 E-value: 1.22e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmeDDSNWY--RAELDGKEGLIPSNYI 53
Cdd:cd12011   2 AVALCNFPSGGPTELSIRMGEQLTILS--EDGDWWkvSSAVTGRECYIPSNYV 52

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212781 [Multi-domain] Cd Length: 58 Bit Score: 38.69 E-value: 1.23e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVtPYH 210
Cdd:cd11847   4 ALWDFKARGDEELSFQAGDQFRIAERSGDWWTALKLDRAGGVVAQGFV-PNN 54

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 3; GRAF3 is also called Rho GTPase activating protein 42 (ARHGAP42) or ARHGAP10-like. Though its function has not been characterized, it may be a GAP with activity towards RhoA and Cdc42, based on its similarity to GRAF and GRAF2. It contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212999 Cd Length: 55 Bit Score: 38.50 E-value: 1.33e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12066   1 QAKAMYSCKAEHSHELSFPQGAIFSNVYPSVEPGWLKATYEGKTGLVPENYVV 53

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212939 [Multi-domain] Cd Length: 56 Bit Score: 38.49 E-value: 1.47e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGE--IGNRKGIFPATYVTP 208
Cdd:cd12006   2 LFVALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEARslTTGETGYIPSNYVAP 56

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or non-receptor) PTK and is the vertebrate homolog of the oncogenic protein (v-Src) from Rous sarcoma virus. Together with other Src subfamily proteins, it is involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. Src also play a role in regulating cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Elevated levels of Src kinase activity have been reported in a variety of human cancers. Several inhibitors of Src have been developed as anti-cancer drugs. Src is also implicated in acute inflammatory responses and osteoclast function. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212941 [Multi-domain] Cd Length: 56 Bit Score: 38.55 E-value: 1.55e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELD-GKEGLIPSNYI 53
Cdd:cd12008   3 VALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHSLTtGQTGYIPSNYV 53

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212698 [Multi-domain] Cd Length: 54 Bit Score: 38.40 E-value: 1.55e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILnmeDDS-NWYRAE-LDGKEGLIPSNYIEM 55
Cdd:cd11764   2 VRVLYDFTARNSKELSVLKGEYLEVL---DDSrQWWKVRnSRGQVGYVPHNILEP 53

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1); MPP1, also called 55 kDa erythrocyte membrane protein (p55), is a ubiquitously-expressed scaffolding protein that plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. It was originally identified as an erythrocyte protein that stabilizes the actin cytoskeleton to the plasma membrane by forming a complex with 4.1R protein and glycophorin C. MPP1 is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains the three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213013 Cd Length: 62 Bit Score: 38.40 E-value: 1.57e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 157 VQALYDFVP--------QESGeLDFRRGDVITVTDRSDENWWNGEIGN 196
Cdd:cd12080   2 MRAQFDYDPkkdnlipcKEAG-LKFQTGDIIQIINKDDSNWWQGRVEG 48

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212867 [Multi-domain] Cd Length: 59 Bit Score: 38.44 E-value: 1.58e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENWWNG--EIGNRKGIFPATYV 206
Cdd:cd11934   6 RAVYDYNAADEDEVSFQDGDTIVNVQQIDDGWMYGtvERTGDTGMLPANYV 56

First Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212860 Cd Length: 54 Bit Score: 38.39 E-value: 1.69e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILkILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11927   3 AKALYNYEGKEPGDLKFSKGDII-ILRRQVDENWYHGEVNGIHGFFPTNFVQI 54

Src homology 3 domain of Endophilin-B1; Endophilin-B1, also called Bax-interacting factor 1 (Bif-1) or SH3GLB1 (SH3-domain GRB2-like endophilin B1), is localized mainly to the Golgi apparatus. It is involved in the regulation of many biological events including autophagy, tumorigenesis, nerve growth factor (NGF) trafficking, neurite outgrowth, mitochondrial outer membrane dynamics, and cell death. Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. Endophilin-B1 forms homo- and heterodimers (with endophilin-B2) through its BAR domain. It interacts with amphiphysin 1 and dynamin 1 through its SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212878 Cd Length: 61 Bit Score: 38.47 E-value: 1.82e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYV 206
Cdd:cd11945   7 RVLYDYDAANSTELSLLADEVITVYSVPgmDSDWLMGERGNQKGKVPITYL 57

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212698 [Multi-domain] Cd Length: 54 Bit Score: 38.01 E-value: 1.84e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSdENWW-----NGEIgnrkGIFPATYVTPY 209
Cdd:cd11764   1 YVRVLYDFTARNSKELSVLKGEYLEVLDDS-RQWWkvrnsRGQV----GYVPHNILEPY 54

Src Homology 3 domain of Membrane Protein, Palmitoylated 4 (or MAGUK p55 subfamily member 4); MPP4, also called Disks Large homolog 6 (DLG6) or Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 5 protein (ALS2CR5), is a retina-specific scaffolding protein that plays a role in organizing presynaptic protein complexes in the photoreceptor synapse, where it localizes to the plasma membrane. It is required in the proper localization of calcium ATPases and for maintenance of calcium homeostasis. MPP4 is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212967 Cd Length: 61 Bit Score: 38.34 E-value: 1.88e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 23344846 157 VQALYDFVPQESGE-------LDFRRGDVITVTDRSDENWW 190
Cdd:cd12034   2 VRAMVDYWPQQDPSipcadagLPFRKGDILQIVDQNDSLWW 42

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198208 Cd Length: 95 Bit Score: 39.28 E-value: 1.93e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846  60 WYYGRITRADAEKLLSN--KHEGAFLIRiSESSPGDFSLSVKCPDGVQHFKVLRDAQSKFFL-WVVKFNSLNELVEY 133
Cdd:cd10345   2 WFHGKISREESEQIVLIgsKTNGKFLIR-ARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIpEGKKFDTLWQLVEH 77

N-terminal Src homology 2 (SH2) domain found in Spt6; N-terminal SH2 domain in Spt6. Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II. Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198174 Cd Length: 85 Bit Score: 38.76 E-value: 1.95e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 23344846  65 ITRADAEKLLSNKHEGAFLIRISESSPGDFSLSVKCPDGV-QHFKVLRDAQSKFF-----LWV--VKFNSLNELVEYH 134
Cdd:cd09918   8 VNYKQAEAYLKSKDVGEVVIRPSSKGVDHLTVTWKVADGVyQHIDIEELNKENPFslgkeLIIggEEYEDLDEIIARF 85

Src homology 3 domain of the Rho guanine nucleotide exchange factor, ephexin-1 (also called NGEF or ARHGEF27); Ephexin-1, also called NGEF (neuronal GEF) or ARHGEF27, activates RhoA, Tac1, and Cdc42 by exchanging bound GDP for free GTP. It is expressed mainly in the brain in a region associated with movement control. It regulates the stability of postsynaptic acetylcholine receptor (AChR) clusters and thus, plays a critical role in the maturation and neurotransmission of neuromuscular junctions. Ephexin-1 directly interacts with the ephrin receptor EphA4 and their coexpression enhances the ability of ephexin-1 to activate RhoA. It is required for normal axon growth and EphA-induced growth cone collapse. Ephexin-1 contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212872 [Multi-domain] Cd Length: 55 Bit Score: 38.00 E-value: 2.06e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEI--GNRKGIFPATYV 206
Cdd:cd11939   2 VQCVHPYVSQEPDELSLELADVLNILDKTDDGWIFGERlhDQERGWFPSSVV 53

Src Homology 3 domain of Insulin Receptor tyrosine kinase Substrate p53, Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2 (BAIAP2)-Like proteins, and similar proteins; Proteins in this family include IRSp53, BAIAP2L1, BAIAP2L2, and similar proteins. They all contain an Inverse-Bin/Amphiphysin/Rvs (I-BAR) or IMD domain in addition to the SH3 domain. IRSp53, also known as BAIAP2, is a scaffolding protein that takes part in many signaling pathways including Cdc42-induced filopodia formation, Rac-mediated lamellipodia extension, and spine morphogenesis. IRSp53 exists as multiple splicing variants that differ mainly at the C-termini. BAIAP2L1, also called IRTKS (Insulin Receptor Tyrosine Kinase Substrate), serves as a substrate for the insulin receptor and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. IRSp53 and IRTKS also mediate the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. BAIAP2L2 co-localizes with clathrin plaques but its function has not been determined. The SH3 domains of IRSp53 and IRTKS have been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212713 [Multi-domain] Cd Length: 57 Bit Score: 37.69 E-value: 2.57e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846 155 MLVQALYDFVPQESGELDFRRGDVIT-VTDRSDENWWNGE--IGNRKGIFPATYVTP 208
Cdd:cd11779   1 PRVKALYPHAAGGETQLSFEEGDVITlLGPEPRDGWHYGEneRSGRRGWFPIAYTEP 57

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212866 [Multi-domain] Cd Length: 58 Bit Score: 37.68 E-value: 2.65e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   5 AKHDFSATADDELSFRKTQIlkILNMED-DSNWYRAELD--GKEGLIPSNYIE 54
Cdd:cd11933   6 AMYDYRAADDDEVSFKDGDT--IVNVQTiDEGWMYGTVQrtGKTGMLPANYVE 56

Src homology 3 domain of Alpha Spectrin; Spectrin is a major structural component of the red blood cell membrane skeleton and is important in erythropoiesis and membrane biogenesis. It is a flexible, rope-like molecule composed of two subunits, alpha and beta, which consist of many spectrin-type repeats. Alpha and beta spectrin associate to form heterodimers and tetramers; spectrin tetramer formation is critical for red cell shape and deformability. Defects in alpha spectrin have been associated with inherited hemolytic anemias including hereditary spherocytosis (HSp), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP). Alpha spectrin contains a middle SH3 domain and a C-terminal EF-hand binding motif in addition to multiple spectrin repeats. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212742 [Multi-domain] Cd Length: 53 Bit Score: 37.85 E-value: 2.70e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11808   3 VALYDYQEKSPREVSMKKGDILTLLN-SSNKDWWKVEVNDRQGFVPAAYVK 52

First Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the first SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212948 Cd Length: 53 Bit Score: 37.40 E-value: 2.91e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846 162 DFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12015   7 DYKKQQPNEISLRAGDVVDVIEKNENGWWFVSLEDEQGWVPATYLEP 53

Src Homology 3 domain of SH3 domain-binding protein 4; SH3 domain-binding protein 4 (SH3BP4) is also called transferrin receptor trafficking protein (TTP). SH3BP4 is an endocytic accessory protein that interacts with endocytic proteins including clathrin and dynamin, and regulates the internalization of the transferrin receptor (TfR). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212691 Cd Length: 52 Bit Score: 37.31 E-value: 3.23e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11757   2 VVAIKDYCPTNFTTLKFSKGDHLYVLDTSGGEWWYAHNTTEMGYIPSSYV 51

Src Homology 3 domain of Myosin XVb; Myosin XVb, also called KIAA1783, was named based on its similarity with myosin XVa. It is a transcribed and unprocessed pseudogene whose predicted amino acid sequence contains mutated or deleted amino acid residues that are normally conserved and important for myosin function. The related myosin XVa is important for normal growth of mechanosensory stereocilia of inner ear hair cells. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 213001 Cd Length: 55 Bit Score: 37.55 E-value: 3.39e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12068   2 VVALRSYITDDKSLLSFHRGDLIKLLPMAglEPGWQFGSTGGRSGLFPADIVQP 55

Third Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212750 [Multi-domain] Cd Length: 51 Bit Score: 37.39 E-value: 3.47e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDGKEGLIPSNYI 53
Cdd:cd11816   2 CVARFDFEGEQEDELSFSEGDVITLKEYVGEE-WAKGELNGKIGIFPLNFV 51

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Neural precursor cell Expressed, Developmentally Down-regulated 9; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212935 Cd Length: 57 Bit Score: 37.66 E-value: 3.48e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKIL--NMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd12002   2 ARALYDNVPECAEELAFRKGDILTVIeqNTGGLEGWWLCSLHGRQGIAPGNRLKL 56

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 37.34 E-value: 3.58e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKI-LNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11836   4 ALYAFEARNPDEISFQPGDIIQVdESQVAEPGWLAGELKGKTGWFPANYVE 54

First Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the first C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212845 [Multi-domain] Cd Length: 55 Bit Score: 37.20 E-value: 3.89e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWW----NGeiGNRKGIFPATYV 206
Cdd:cd11912   2 AKVLYDYTASGDDEVSISEGEEVTVLEPDDGSGWtkvrNG--SGEEGLVPTSYI 53

Second Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212708 [Multi-domain] Cd Length: 52 Bit Score: 37.06 E-value: 3.99e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKE-GLIPSNYI 53
Cdd:cd11774   2 AKALYDYDKQTEEELSFNEGDTLDVYD-DSDSDWILVGFNGTQfGFVPANYI 52

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 37.32 E-value: 4.20e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   7 HDFSATADDELSFRKTQILKILNMEdDSNWYRAELDGKE-----GLIPSNYIEM 55
Cdd:cd11839   6 APFTATAENQLSLAVGQLVLVRKKS-PSGWWEGELQARGkkrqiGWFPANYVKL 58

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 37.25 E-value: 4.33e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 23344846  14 DDELSFRKTQILKIlNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12054  14 EDELELKVGDIIDI-NEEVEEGWWSGTLNGKSGLFPSNFVK 53

Second Src homology 3 domain (or SH3B) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212923 [Multi-domain] Cd Length: 52 Bit Score: 36.94 E-value: 4.34e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   9 FSATADDELSFRKTQILKILnmEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11990   8 WTAKKDNHLNFSKNDIITVL--EQQENWWFGEVHGGRGWFPKSYVKL 52

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 37.09 E-value: 4.51e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12046   3 VALFSYEASQPEDLEFQKGDVILVLSKVNE-DWLEGQCKGKIGIFPSAFVE 52

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1; SKAP1, also called SKAP55 (Src kinase-associated protein of 55kDa), is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212977 Cd Length: 53 Bit Score: 37.15 E-value: 4.84e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDE--NWWNGEIGNRKGIFPATYV 206
Cdd:cd12044   3 QGLWDCFGDNPDELSFQRGDLIYILSKEYNmyGWWVGELNGIVGIVPKDYL 53

Src Homology 3 domain of Disks large homolog proteins; The DLG-like proteins are scaffolding proteins that cluster at synapses and are also called PSD (postsynaptic density)-95 proteins or SAPs (synapse-associated proteins). They play important roles in synaptic development and plasticity, cell polarity, migration and proliferation. They are members of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG-like proteins contain three PDZ domains and varying N-terminal regions. All DLG proteins exist as alternatively-spliced isoforms. Vertebrates contain four DLG proteins from different genes, called DLG1-4. DLG4 and DLG2 are found predominantly at postsynaptic sites and they mediate surface ion channel and receptor clustering. DLG3 is found axons and some presynaptic terminals. DLG1 interacts with AMPA-type glutamate receptors and is critical in their maturation and delivery to synapses. The SH3 domain of DLG4 binds and clusters the kainate subgroup of glutamate receptors via two proline-rich sequences in their C-terminal tail. It also binds AKAP79/150 (A-kinase anchoring protein). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212795 [Multi-domain] Cd Length: 61 Bit Score: 37.30 E-value: 4.87e-04

                        10        20        30
                ....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVP-QESG----ELDFRRGDVITVTDRSDENWW 190
Cdd:cd11861   2 VRALFDYDPsRDSGlpsqGLSFKFGDILHVTNASDDEWW 40

Second Src Homology 3 domain (SH3B) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212988 [Multi-domain] Cd Length: 53 Bit Score: 36.90 E-value: 4.91e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 23344846  14 DDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd12055  13 EDELELKVGDIIEVVG-EVEEGWWEGVLNGKTGMFPSNFIK 52

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198274 Cd Length: 97 Bit Score: 38.06 E-value: 5.06e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  53 IEMKNHDWYYGRITRADAEKLL---SNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKV 109
Cdd:cd10411   3 LELSDYPWFHGTLSRVKAAQLVlagGPRSHGLFVIRQSETRPGEYVLTFNFQGKAKHLRL 62

Src homology 3 domain of Rho GTPase-activating proteins 32 and 33, and similar proteins; Members of this family contain N-terminal PX and Src Homology 3 (SH3) domains, a central Rho GAP domain, and C-terminal extensions. RhoGAPs (or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP32 is also called RICS, PX-RICS, p250GAP, or p200RhoGAP. It is a Rho GTPase-activating protein for Cdc42 and Rac1, and is implicated in the regulation of postsynaptic signaling and neurite outgrowth. PX-RICS, a variant of RICS that contain PX and SH3 domains, is the main isoform expressed during neural development. It is involved in neural functions including axon and dendrite extension, postnatal remodeling, and fine-tuning of neural circuits during early brain development. ARHGAP33, also called sorting nexin 26 or TCGAP (Tc10/CDC42 GTPase-activating protein), is widely expressed in the brain where it is involved in regulating the outgrowth of axons and dendrites and is regulated by the protein tyrosine kinase Fyn. It is translocated to the plasma membrane in adipocytes in response to insulin and may be involved in the regulation of insulin-stimulated glucose transport. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212769 [Multi-domain] Cd Length: 54 Bit Score: 37.04 E-value: 5.31e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 23344846 166 QESGELDFRRGDVITVTD---RSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11835  11 QAPDELSLEVGDIVSVIDmppPEESTWWRGKKGFQVGFFPSECV 54

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 36.88 E-value: 5.41e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDG-----KEGLIPSNY 52
Cdd:cd11883   3 VALYDFTPKSKNQLSFKAGDIIYVLN-KDPSGWWDGVIISssgkvKRGWFPSNY 55

First Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The first SH3 domain of Nck proteins preferentially binds the PxxDY sequence, which is present in the CD3e cytoplasmic tail. This binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212699 [Multi-domain] Cd Length: 51 Bit Score: 36.63 E-value: 5.55e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSdENWWNGEIG-NRKGIFPATYV 206
Cdd:cd11765   1 YVVAKYDYTAQGDQELSIKKNEKLTLLDDS-KHWWKVQNSsNQTGYVPSNYV 51

Second Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212812 [Multi-domain] Cd Length: 56 Bit Score: 36.93 E-value: 5.56e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 160 LYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNR---KGIFPATYVT 207
Cdd:cd11879   5 LYDFKAERPDELDAKAGDAIIICAHSNYEWFVAKPIGRlggPGLIPVSFVE 55

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198245 Cd Length: 98 Bit Score: 37.73 E-value: 5.72e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  59 DWYYGRITRADAEKLLSNKHEGAFLIRisESSPGD--FSLSVKCPDGVQHFKVLRDAQsKFFL--WVVKFNSLNELVEY 133
Cdd:cd10382  11 GFYWGPLSVEEAHAKLKREPVGTFLIR--DSRQKNcfFALSVKMASGPVSIRILFKAG-KFSLdgSKESFDCLFKLLEH 86

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 36.91 E-value: 5.81e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 161 YDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11902   7 FAYVAEREDELSLVKGSRVTVMEKCSDGWWRGSYNGQIGWFPSNYV 52

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212917 Cd Length: 52 Bit Score: 36.85 E-value: 5.81e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11984   5 AVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

Src Homology 3 domain of TXK, also called Resting lymphocyte kinase (Rlk); TXK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. Rlk is expressed in T-cells and mast cell lines, and is a key component of T-cell receptor (TCR) signaling. It is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212840 [Multi-domain] Cd Length: 55 Bit Score: 36.86 E-value: 6.07e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   1 MEAIAKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11907   1 IQVKALYDFLPREPSNLALKRAEEYLILEQYDPHWWKARDRYGNEGLIPSNYV 53

Third Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the third SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212950 Cd Length: 53 Bit Score: 36.66 E-value: 6.26e-04

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 23344846 171 LDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12017  16 ISFQKGQKVEVIDKNPSGWWYVKIDGKEGWAPSSYI 51

First Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212862 Cd Length: 54 Bit Score: 36.84 E-value: 6.31e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   3 AIAKHDFSATADDELSFRKTQILkILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11929   3 AKALCNYRGHNPGDLKFNKGDVI-LLRRQLDENWYLGEINGVSGIFPASSVEV 54

First Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The first SH3 domain of Nck2 binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212832 [Multi-domain] Cd Length: 58 Bit Score: 36.65 E-value: 6.74e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 153 EEMLVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11899   2 EEVIVIAKWDYTAQQDQELDIKKNERLWLLDDSKTWWRVRNAANRTGYVPSNYV 55

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 36.59 E-value: 6.85e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   3 AIAKHDFSATADDELSFRKTQILKILNMEdDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11828   2 AEALWDHVTMDPEELGFKAGDVIEVLDMS-DKDWWWGSIRDEEGWFPASFV 51

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 36.55 E-value: 6.93e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNMEDDSnWYRAELDG-----KEGLIPSNYIE 54
Cdd:cd11887   5 KALYPYESDHEDDLNFDVGQLITVTEEEDAD-WYFGEYVDsngntKEGIFPKNFVE 59

Second Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the second SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213009 [Multi-domain] Cd Length: 54 Bit Score: 36.55 E-value: 7.08e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12076   5 VIYPYTARDQDEINLEKGAVVEVIQKNLEGWWKIRYQGKEGWAPASYL 52

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198183 Cd Length: 121 Bit Score: 38.06 E-value: 7.50e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23344846  54 EMKNHDWYYGRITRADAEKLL--SNKhEGAFLIRisESSPGD----FSLSVKCPDGVQHFKVLRDAQSKFFLW------V 121
Cdd:cd09929   7 DLLPKEWYAGNIDRKEAEEALrrSNK-DGTFLVR--DSSGKDssqpYTLMVLYNDKVYNIQIRFLENTRQYALgtglrgE 83

                        90
                ....*....|....
gi 23344846 122 VKFNSLNELVEYHR 135
Cdd:cd09929  84 ETFSSVAEIIEHHQ 97

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 36.52 E-value: 7.54e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGK---EGLIPSNY 52
Cdd:cd11821   4 ALYDCQADNDDELTFSEGEIIVVTGEEDD-EWWEGHIEGDpsrRGVFPVSF 53

Src Homology 3 domain of Saccharomyces cerevisiae Nap1-binding protein 2 and similar fungal proteins; This subfamily includes Saccharomyces cerevisiae Nbp2 (Nucleosome assembly protein 1 (Nap1)-binding protein 2), Schizosaccharomyces pombe Skb5, and similar proteins. Nbp2 interacts with Nap1, which is essential for maintaining proper nucleosome structures in transcription and replication. It is also the binding partner of the yeast type II protein phosphatase Ptc1p and serves as a scaffolding protein that brings seven kinases in close contact to Ptc1p. Nbp2 plays a role many cell processes including organelle inheritance, mating hormone response, cell wall stress, mitotic cell growth at elevated temperatures, and high osmolarity. Skb5 interacts with the p21-activated kinase (PAK) homolog Shk1, which is critical for fission yeast cell viability. Skb5 activates Shk1 and plays a role in regulating cell morphology and growth under hypertonic conditions. Nbp2 and Skb5 contain an SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212799 Cd Length: 55 Bit Score: 36.34 E-value: 8.28e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWW--NGEIGNRKGIFPATYV 206
Cdd:cd11865   4 ALYDFEPEHDNELGFAEGQILFILYKHGQGWLiaEDESGGKTGLVPEEFV 53

Src homology 3 domain of JNK-interacting proteins 1 and 2, and similar domains; JNK-interacting proteins (JIPs) function as scaffolding proteins for c-Jun N-terminal kinase (JNK) signaling pathways. They bind to components of Mitogen-activated protein kinase (MAPK) pathways such as JNK, MKK, and several MAP3Ks such as MLK and DLK. There are four JIPs (JIP1-4); all contain a JNK binding domain. JIP1 and JIP2 also contain SH3 and Phosphotyrosine-binding (PTB) domains. Both are highly expressed in the brain and pancreatic beta-cells. JIP1 functions as an adaptor linking motor to cargo during axonal transport and also is involved in regulating insulin secretion. JIP2 form complexes with fibroblast growth factor homologous factors (FHFs), which facilitates activation of the p38delta MAPK. The SH3 domain of JIP1 homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212735 Cd Length: 55 Bit Score: 36.13 E-value: 8.48e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENW---WNGEIGnRKGIFPATYV 206
Cdd:cd11801   4 ALHKFIPRHEDEIELDIGDPVYVEQEADDLWcegTNLRTG-QRGIFPAAYV 53

Src Homology 3 domain of SH3 domain and tetratricopeptide repeat-containing (SH3TC) proteins and similar domains; This subfamily is composed of vertebrate SH3TC proteins and hypothetical fungal proteins containing BAR and SH3 domains. Mammals contain two SH3TC proteins, SH3TC1 and SH3TC2. The function of SH3TC1 is unknown. SH3TC2 is localized in Schwann cells in the peripheral nervous system, where it interacts with Rab11 and plays a role in peripheral nerve myelination. Mutations in SH3TC2 are associated with Charcot-Marie-Tooth disease type 4C, a severe hereditary peripheral neuropathy with symptoms that include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212818 Cd Length: 55 Bit Score: 36.14 E-value: 8.87e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   5 AKHDFSATADDELSFRKTQILKIL-NMEDDSNWY--RAELDGKEGLIPSNYI 53
Cdd:cd11885   4 AKMDFEGVEPGELSFRQGDSIEIIgDLIPGLQWFvgRSKSSGRVGFVPTNHF 55

C-terminal Src Homology 3 domain of Ct10 Regulator of Kinase adaptor proteins; CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers. The C-terminal SH3 domain of CRK has not been shown to bind any target protein; it acts as a negative regulator of CRK function by stabilizing a structure that inhibits the access by target proteins to the N-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212693 [Multi-domain] Cd Length: 57 Bit Score: 36.31 E-value: 9.37e-04

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 23344846 171 LDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11759  20 LALEVGDLVKVTKINVSGQWEGELNGKVGHFPFTHV 55

First Src homology 3 domain (or SH3A) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212920 [Multi-domain] Cd Length: 55 Bit Score: 36.13 E-value: 9.78e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRS--DENWWNGEIGNRKGIFPATY 205
Cdd:cd11987   3 RALYPFEARSHDEITIQPGDIVMVDESQtgEPGWLGGELKGKTGWFPANY 52

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or non-receptor) PTK and is the vertebrate homolog of the oncogenic protein (v-Src) from Rous sarcoma virus. Together with other Src subfamily proteins, it is involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. Src also play a role in regulating cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Elevated levels of Src kinase activity have been reported in a variety of human cancers. Several inhibitors of Src have been developed as anti-cancer drugs. Src is also implicated in acute inflammatory responses and osteoclast function. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212941 [Multi-domain] Cd Length: 56 Bit Score: 36.24 E-value: 9.92e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSDENWW--NGEIGNRKGIFPATYVTP 208
Cdd:cd12008   4 ALYDYESRTETDLSFKKGERLQIVNNTEGDWWlaHSLTTGQTGYIPSNYVAP 55

C-terminal Src Homology 3 domain of NADPH oxidase activator 1; Noxa1 is a homolog of p67phox and is a cytosolic subunit of the nonphagocytic NADPH oxidase complex Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Noxa1 is co-expressed with Nox1 in colon, stomach, uterus, prostate, and vascular smooth muscle cells, consistent with its regulatory role. It does not interact with p40phox, unlike p67phox, making Nox1 activity independent of p40phox, unlike Nox2. Noxa1 contains TPR, PB1, and C-terminal SH3 domains, but lacks the central SH3 domain that is present in p67phox. The TPR domain binds activated GTP-bound Rac. The C-terminal SH3 domain binds the polyproline motif found at the C-terminus of Noxo1, a homolog of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212980 Cd Length: 53 Bit Score: 35.95 E-value: 1.00e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPS 50
Cdd:cd12047   3 VAQHDYSAQGPEDLEFSQGDTIDILS-EVNQEWLEGHCDGRIGIFPK 48

Src Homology 3 domain of fungal BOI-like proteins; This subfamily includes the Saccharomyces cerevisiae proteins BOI1 and BOI2, and similar proteins. They contain an N-terminal SH3 domain, a Sterile alpha motif (SAM), and a Pleckstrin homology (PH) domain at the C-terminus. BOI1 and BOI2 interact with the SH3 domain of Bem1p, a protein involved in bud formation. They promote polarized cell growth and participates in the NoCut signaling pathway, which is involved in the control of cytokinesis. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212819 Cd Length: 55 Bit Score: 36.16 E-value: 1.01e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846   4 IAKHDFSATADDELSFRKTQILKILnmEDDS----NWY--RAELDGKEGLIPSNY 52
Cdd:cd11886   3 IVIHDFNARSEDELTLKPGDKIELI--EDDEefgdGWYlgRNLRTGETGLFPVVF 55

C-terminal Src Homology 3 domain of the p67phox subunit of NADPH oxidase and similar proteins; This subfamily is composed of p67phox, NADPH oxidase activator 1 (Noxa1), and similar proteins. p67phox, also called Neutrophil cytosol factor 2 (NCF-2), and Noxa1 are homologs and are the cytosolic subunits of the phagocytic (Nox2) and nonphagocytic (Nox1) NADPH oxidase complexes, respectively. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox and Noxa1 play regulatory roles. p67phox contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. Noxa1 has a similar domain architecture except it is lacking the N-terminal SH3 domain. The TPR domain of both binds activated GTP-bound Rac, while the C-terminal SH3 domain of p67phox and Noxa1 binds the polyproline motif found at the C-terminus of p47phox and Noxo1, respectively. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212803 [Multi-domain] Cd Length: 53 Bit Score: 35.97 E-value: 1.06e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11870   1 QVVALHRYEAQGPEDLGFREGDTIDVLS-EVNEAWLEGHSDGRVGIFPKCFVV 52

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212792 [Multi-domain] Cd Length: 55 Bit Score: 35.82 E-value: 1.13e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDG-KEGLIPSNYIE 54
Cdd:cd11858   4 ALYDFAGSVANELSLKKDDIVYIVQKEDNGWWLAKKLDEsKEGWVPAAYLE 54

First Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212947 Cd Length: 62 Bit Score: 36.18 E-value: 1.14e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  16 ELSFRKTQILKILNMEDDSNWYRAEL-DGKEGLIPSNYIE 54
Cdd:cd12014  22 ELPLNAGDYVYVYGDMDEDGFYEGELlDGRRGLVPSNFVE 61

Src Homology 3 domain of Melanoma Inhibitory Activity 2 protein; MIA2 is expressed specifically in hepatocytes and its expression is controlled by hepatocyte nuclear factor 1 binding sites in the MIA2 promoter. It inhibits the growth and invasion of hepatocellular carcinomas (HCC) and may act as a tumor suppressor. A mutation in MIA2 in mice resulted in reduced cholesterol and triglycerides. Since MIA2 localizes to ER exit sites, it may function as an ER-to-Golgi trafficking protein that regulates lipid metabolism. MIA2 contains an N-terminal SH3-like domain, similar to MIA. It is a member of the recently identified family that also includes MIA, MIAL, and MIA3 (also called TANGO). MIA is a single domain protein that adopts a SH3 domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

Pssm-ID: 212825 Cd Length: 73 Bit Score: 36.35 E-value: 1.18e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITV---TDRSDENWWNGEIGNRKGIFPATYVT 207
Cdd:cd11892  14 VQAIRDYRGPDCRYLSFKKGDEIIVyykLSGKREDLWAGSTGKEFGYFPKDAVK 67

Src homology 3 domain of JNK-interacting protein 1; JNK-interacting protein 1 (JIP1) is also called Islet-brain 1 (IB1) or Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1). It is highly expressed in neurons, where it functions as an adaptor linking motor to cargo during axonal transport. It also affects microtubule dynamics in neurons. JIP1 is also found in pancreatic beta-cells, where it is involved in regulating insulin secretion. In addition to a JNK binding domain, JIP1 also contains SH3 and Phosphotyrosine-binding (PTB) domains. Its SH3 domain homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212876 Cd Length: 55 Bit Score: 36.12 E-value: 1.19e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVTDRSDENW---WNGEIGNRkGIFPATY 205
Cdd:cd11943   3 RAVFRFVPRHPDELELEVDDPLLVEVQAEDYWyeaYNMRTGAR-GIFPAYY 52

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 36.15 E-value: 1.27e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMED----DSNWYRA--ELDGKEGLIPSNYIE 54
Cdd:cd11790   7 ATHDYTAEDTDELTFEKGDVILVIPFDDpeeqDEGWLMGvkESTGCRGVFPENFTE 62

Second N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212729 Cd Length: 54 Bit Score: 35.89 E-value: 1.40e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 23344846 162 DFVPQESGELDFRRGDVITVTDRSDENWWNGEI-GNRKGIFPATYV 206
Cdd:cd11795   7 AFTSQEPGHLNLQRGDLVELTGTTDSGWLQGRScWGSSGFFPSSCV 52

Src Homology 3 domain of Membrane Protein, Palmitoylated 5 (or MAGUK p55 subfamily member 5); MPP5, also called PALS1 (Protein associated with Lin7) or Nagie oko protein in zebrafish or Stardust in Drosophila, is a scaffolding protein which associates with Crumbs homolog 1 (CRB1), CRB2, or CRB3 through its PDZ domain and with PALS1-associated tight junction protein (PATJ) or multi-PDZ domain protein 1 (MUPP1) through its L27 domain. The resulting tri-protein complexes are core proteins of the Crumb complex, which localizes at tight junctions or subapical regions, and is involved in the maintenance of apical-basal polarity in epithelial cells and the morphogenesis and function of photoreceptor cells. MPP5 is critical for the proper stratification of the retina and is also expressed in T lymphocytes where it is important for TCR-mediated activation of NFkB. Drosophila Stardust exists in several isoforms, some of which show opposing functions in photoreceptor cells, which suggests that the relative ratio of different Crumbs complexes regulates photoreceptor homeostasis. MPP5 contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212969 Cd Length: 63 Bit Score: 35.85 E-value: 1.49e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 23344846 157 VQALYDFVP--------QESGeLDFRRGDVITVTDRSDENWW 190
Cdd:cd12036   2 VRAHFDYDPeddpyipcRELG-LSFQKGDILHVISQEDPNWW 42

Src homology 3 domain of SH3 protein interacting with Nck, 90 kDa (SPIN90); SPIN90 is also called NCK interacting protein with SH3 domain (NCKIPSD), Dia-interacting protein (DIP), 54 kDa vimentin-interacting protein (VIP54), or WASP-interacting SH3-domain protein (WISH). It is an F-actin binding protein that regulates actin polymerization and endocytosis. It associates with the Arp2/3 complex near actin filaments and determines filament localization at the leading edge of lamellipodia. SPIN90 is expressed in the early stages of neuronal differentiation and plays a role in regulating growth cone dynamics and neurite outgrowth. It also interacts with IRSp53 and regulates cell motility by playing a role in the formation of membrane protrusions. SPIN90 contains an N-terminal SH3 domain, a proline-rich domain, and a C-terminal VCA (verprolin-homology and cofilin-like acidic) domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212783 [Multi-domain] Cd Length: 53 Bit Score: 35.37 E-value: 1.56e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 23344846   5 AKHDFSATADDELSFRKTQILKILNMEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11849   4 ALYDFKSAEPNTLSFSEGETFLLLERSNAHWWLVTNHSGETGYVPANYVK 53

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 35.37 E-value: 1.63e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   2 EAIAKHDFSATADDELSFRKTQilKILNMEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11992   1 EYIALYPYSSSEPGDLTFNEGE--EILVTQKDGEWWTGSIEDRTGIFPSNYV 50

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 35.38 E-value: 1.74e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 23344846  17 LSFRKTQILKILNME--DDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11884  16 LSFHKGDVIKLLPKEgpLDPGWLFGTLDGRSGAFPKEYVQ 55

Src Homology 3 domain of Class A and B Dedicator of Cytokinesis proteins; DOCK proteins are atypical guanine nucleotide exchange factors (GEFs) that lack the conventional Dbl homology (DH) domain. They are divided into four classes (A-D) based on sequence similarity and domain architecture: class A includes Dock1, 2 and 5; class B includes Dock3 and 4; class C includes Dock6, 7, and 8; and class D includes Dock9, 10 and 11. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). The DHR-1 domain binds phosphatidylinositol-3,4,5-triphosphate while DHR-2 contains the catalytic activity for Rac and/or Cdc42. This subfamily includes only Class A and B DOCKs, which also contain an SH3 domain at the N-terminal region and a PxxP motif at the C-terminus. Class A/B DOCKs are mostly specific GEFs for Rac, except Dock4 which activates the Ras family GTPase Rap1, probably indirectly through interaction with Rap regulatory proteins. The SH3 domain of class A/B DOCKs have been shown to bind Elmo, a scaffold protein that promotes GEF activity of DOCKs by releasing DHR-2 autoinhibition by the intramolecular SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212805 [Multi-domain] Cd Length: 56 Bit Score: 35.25 E-value: 1.90e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846 159 ALYDFVPQESGELDFRRGDVITVTDRSdENWWNG-EIGNR--KGIFPATYV 206
Cdd:cd11872   4 AIYNFQGDGEHQLSLQVGDTVQILEEC-EGWYRGfSLRNKslKGIFPKSYV 53

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1); MPP1, also called 55 kDa erythrocyte membrane protein (p55), is a ubiquitously-expressed scaffolding protein that plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. It was originally identified as an erythrocyte protein that stabilizes the actin cytoskeleton to the plasma membrane by forming a complex with 4.1R protein and glycophorin C. MPP1 is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains the three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213013 Cd Length: 62 Bit Score: 35.31 E-value: 2.02e-03

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 23344846  17 LSFRKTQILKILNmEDDSNWY--RAELDGKE--GLIPS 50
Cdd:cd12080  23 LKFQTGDIIQIIN-KDDSNWWqgRVEGSGEEsaGLIPS 59

Second Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212945 Cd Length: 62 Bit Score: 35.35 E-value: 2.05e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 23344846 159 ALYDFVPQ--------ESGELDFRRGDVITV-TDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12012   4 ALFDYDPLtmspnpdaAEEELPFKEGQLIKVyGDKDADGFYLGEINGRRGLVPCNMV 60

Src homology 3 domain of RUN and SH3 domain-containing protein 2; RUSC2, also called Iporin or Interacting protein of Rab1, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. RUSC proteins are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212890 Cd Length: 52 Bit Score: 35.28 E-value: 2.11e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 23344846  11 ATADDELSFRKTQILKILNmEDDSNWYRAELDGKEGLIPSNYI 53
Cdd:cd11957  10 ATEPGQLSFNKGDILQVLS-RADGDWLRCSLGPDSGLVPIAYV 51

Second or C-terminal Src homology 3 domain of NADPH oxidase (Nox) Organizing protein 1; Nox Organizing protein 1 (NoxO1) is a critical regulator of enzyme kinetics of the nonphagocytic NADPH oxidase Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Nox1 is expressed in colon, stomach, uterus, prostate, and vascular smooth muscle cells. NoxO1 is involved in targeting activator subunits (such as NoxA1) to Nox1. It is co-localized with Nox1 in the membranes of resting cells and directs the subcellular localization of Nox1. NoxO1 contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), and a C-terminal proline-rich region (PRR). This model characterizes the second SH3 domain (or C-SH3) of NoxO1. The tandem SH3 domains of NoxO1 interact with the PRR of p22phox, which also complexes with Nox1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212957 Cd Length: 53 Bit Score: 35.01 E-value: 2.18e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 23344846 166 QESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYVTP 208
Cdd:cd12024  11 QKEDELSVPAGVVVEVLQKSDNGWWLIRYNGRAGYVPSMYLQP 53

Src Homology 3 domain of the p85 regulatory subunit of Class IA Phosphatidylinositol 3-kinases; Class I PI3Ks convert PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. They are heterodimers and exist in multiple isoforms consisting of one catalytic subunit (out of four isoforms) and one of several regulatory subunits. Class IA PI3Ks associate with the p85 regulatory subunit family, which contains SH3, RhoGAP, and SH2 domains. The p85 subunits recruit the PI3K p110 catalytic subunit to the membrane, where p110 phosphorylates inositol lipids. Vertebrates harbor two p85 isoforms, called alpha and beta. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212710 Cd Length: 72 Bit Score: 35.56 E-value: 2.20e-03

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITV---------------TDRSDENWWNG--EIGNRKGIFPATYV 206
Cdd:cd11776   4 RALYDYEKERDEDIILKTGDVLVVenpellalgvpdgkeTVPKPEGWLEGknERTGERGDFPGTYV 69

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 2; SKAP2, also called SKAP55-Related (SKAP55R) or SKAP55 homolog (SKAP-HOM or SKAP55-HOM), is an immune cell-specific adaptor protein that plays an important role in adhesion and migration of B-cells and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), YopH, SHPS1, and HPK1. SKAP2 has also been identified as a substrate for lymphoid-specific tyrosine phosphatase (Lyp), which has been implicated in a wide variety of autoimmune diseases. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. Like SKAP1, SKAP2 is expected to bind primarily to a proline-rich region of ADAP through its SH3 domain; its degradation may be regulated by ADAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212978 Cd Length: 53 Bit Score: 35.26 E-value: 2.24e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDS-NWYRAELDGKEGLIPSNYI 53
Cdd:cd12045   7 DCTGDQPDELSFKRGDTIYILSKEYNRfGWWVGEMKGTIGLVPKAYI 53

Src homology 3 domain of Lck Protein Tyrosine Kinase; Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212938 [Multi-domain] Cd Length: 54 Bit Score: 35.18 E-value: 2.52e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDEnWWNGE--IGNRKGIFPATYV 206
Cdd:cd12005   1 LVVALYSYEPSHDGDLGFEKGEKLRILEQSGE-WWKAQslTTGQEGFIPFNFV 52

Src Homology 3 domain of the p85alpha regulatory subunit of Class IA Phosphatidylinositol 3-kinases; Class I PI3Ks convert PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. They are heterodimers and exist in multiple isoforms consisting of one catalytic subunit (out of four isoforms) and one of several regulatory subunits. Class IA PI3Ks associate with the p85 regulatory subunit family, which contains SH3, RhoGAP, and SH2 domains. The p85 subunits recruit the PI3K p110 catalytic subunit to the membrane, where p110 phosphorylates inositol lipids. Vertebrates harbor two p85 isoforms, called alpha and beta. In addition to regulating the p110 subunit, p85alpha interacts with activated FGFR3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212843 Cd Length: 75 Bit Score: 35.26 E-value: 2.80e-03

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846 158 QALYDFVPQESGELDFRRGDVITVT--------------DRSDE-NWWNG--EIGNRKGIFPATYV 206
Cdd:cd11910   5 RALYDYKKEREEDIDLHLGDILTVNkgsllalgfsegqeARPEEiGWLNGynETTGERGDFPGTYV 70

Src Homology 3 domain of Disks Large homolog 4; DLG4, also called postsynaptic density-95 (PSD95) or synapse-associated protein 90 (SAP90), is a scaffolding protein that clusters at synapses and plays an important role in synaptic development and plasticity. It is responsible for the membrane clustering and retention of many transporters and receptors such as potassium channels and PMCA4b, a P-type ion transport ATPase, among others. DLG4 is a member of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG4 contains three PDZ domains. The SH3 domain of DLG4 binds and clusters the kainate subgroup of glutamate receptors via two proline-rich sequences in their C-terminal tail. It also binds AKAP79/150 (A-kinase anchoring protein). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212963 Cd Length: 66 Bit Score: 35.29 E-value: 2.85e-03

                        10        20        30
                ....*....|....*....|....*....|....*....
gi 23344846 157 VQALYDFVPQE-----SGELDFRRGDVITVTDRSDENWW 190
Cdd:cd12030   4 IRALFDYDKTKdcgflSQALSFRFGDVLHVIDAGDEEWW 42

First Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The first SH3 domain of Nck1 binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212833 [Multi-domain] Cd Length: 59 Bit Score: 35.08 E-value: 2.99e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 153 EEMLVQALYDFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd11900   1 EEVVVVAKFDYVAQQDQELDIKKNERLWLLDDSKSWWRVRNAMNKTGFVPSNYV 54

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1)-like proteins; This subfamily includes MPP1, CASK (Calcium/calmodulin-dependent Serine protein Kinase), Caenorhabditis elegans lin-2, and similar proteins. MPP1 and CASK are scaffolding proteins from the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). In addition, they also have the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. CASK and lin-2 also contain an N-terminal calmodulin-dependent kinase (CaMK)-like domain and two L27 domains. MPP1 is ubiquitously-expressed and plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. CASK is highly expressed in the mammalian nervous system and plays roles in synaptic protein targeting, neural development, and gene expression regulation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212968 Cd Length: 62 Bit Score: 35.10 E-value: 3.00e-03

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 23344846  17 LSFRKTQILKILNmEDDSNWYRAELDGKE----GLIPS 50
Cdd:cd12035  23 IAFKTGDILQIIS-KDDHNWWQARKPGASkepaGLIPS 59

Src Homology 3 domain of Sorting nexin 9; Sorting nexin 9 (SNX9), also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212831 Cd Length: 57 Bit Score: 34.84 E-value: 3.05e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 23344846   7 HDFSATA-DDELSFRKTQILKILNMEDDSNWYRAE-LDGKEGLIPSNYIEM 55
Cdd:cd11898   6 YDFAAEPgNNELTVKEGEIITVTNPNVGGGWIEAKnSQGERGLVPTDYVEI 56

Src homology 3 domain of the Rho guanine nucleotide exchange factors ARHGEF5 and ARHGEF19; ARHGEF5, also called ephexin-3 or TIM (Transforming immortalized mammary oncogene), is a potent activator of RhoA and it plays roles in regulating cell shape, adhesion, and migration. It binds to the SH3 domain of Src and is involved in regulating Src-induced podosome formation. ARHGEF19, also called ephexin-2 or WGEF (weak-similarity GEF), is highly expressed in the intestine, liver, heart and kidney. It activates RhoA, Cdc42, and Rac 1, and has been shown to activate RhoA in the Wnt-PCP (planar cell polarity) pathway. It is involved in the regulation of cell polarity and cytoskeletal reorganization. ARHGEF5 and ARHGEF19 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212873 Cd Length: 55 Bit Score: 34.77 E-value: 3.08e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVTDRSDENWWNG-EIGNR-KGIFPATYVTP 208
Cdd:cd11940   2 VQCIRSYKAQENDELTLEKADIIMVRQQSSDGWLEGvRLSDGeRGWFPQSHVEE 55

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 34.59 E-value: 3.22e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 23344846   3 AIAKHDFSATADDELSFRKTQilKILNMEDDSN-WYRAELDGKEGLIPSNYI 53
Cdd:cd11902   3 AFVKFAYVAEREDELSLVKGS--RVTVMEKCSDgWWRGSYNGQIGWFPSNYV 52

Src Homology 3 domain of Membrane Protein, Palmitoylated 6 (or MAGUK p55 subfamily member 6); MPP6, also called Veli-associated MAGUK 1 (VAM-1) or PALS2, is a scaffolding protein that binds to Veli-1, a homolog of Caenorhabditis Lin-7. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212971 Cd Length: 61 Bit Score: 35.04 E-value: 3.22e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846 162 DFVPQESGELDFRRGDVITVTDRSDENWWNG---EIGNRKGIFPATYV 206
Cdd:cd12038  14 NLIPCKEAGLKFSKGEILQIVNREDPNWWQAshvKEGGSAGLIPSQFL 61

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 34.57 E-value: 3.44e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQIlkILNMEDDSNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11991   1 EYVAMYTYESNEQGDLTFQQGDV--ILVTKKDGDWWTGTVGDKTGVFPSNYVRP 52

Src Homology 3 domain of Saccharomyces cerevisiae Nap1-binding protein 2 and similar fungal proteins; This subfamily includes Saccharomyces cerevisiae Nbp2 (Nucleosome assembly protein 1 (Nap1)-binding protein 2), Schizosaccharomyces pombe Skb5, and similar proteins. Nbp2 interacts with Nap1, which is essential for maintaining proper nucleosome structures in transcription and replication. It is also the binding partner of the yeast type II protein phosphatase Ptc1p and serves as a scaffolding protein that brings seven kinases in close contact to Ptc1p. Nbp2 plays a role many cell processes including organelle inheritance, mating hormone response, cell wall stress, mitotic cell growth at elevated temperatures, and high osmolarity. Skb5 interacts with the p21-activated kinase (PAK) homolog Shk1, which is critical for fission yeast cell viability. Skb5 activates Shk1 and plays a role in regulating cell morphology and growth under hypertonic conditions. Nbp2 and Skb5 contain an SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212799 Cd Length: 55 Bit Score: 34.41 E-value: 3.83e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNmEDDSNWYRAELD--GKEGLIPSNYIEM 55
Cdd:cd11865   1 RAVALYDFEPEHDNELGFAEGQILFILY-KHGQGWLIAEDEsgGKTGLVPEEFVSY 55

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP)1; The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX[VI], which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198205 Cd Length: 103 Bit Score: 35.77 E-value: 3.91e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23344846  60 WYYGRITRADAEKLL-SNKHEGAFLIRISESSPGDFSLSVKCPDGVQHFKVLRDAQSKF 117
Cdd:cd10342   5 VYHGKISRETGEKLLlATGLDGSYLLRDSESVPGVYCLCVLYHGYIYTYRVSQTETGSW 63

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212986 Cd Length: 56 Bit Score: 34.43 E-value: 4.81e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846 154 EMLVQALYDFVPQEsgELDFRRGDVI-TVTDRSDENWWNGEIGNRKGIFPATYV 206
Cdd:cd12053   1 EYIVEYDYDAVHED--ELTIRVGEIIrNVKKLEEEGWLEGELNGRRGMFPDNFV 52

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 33.92 E-value: 5.59e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 23344846   2 EAIAKHDFSATADDELSFRKTQILKILNMEDdsNWYRAELDGKEGLIPSNYIEM 55
Cdd:cd11989   1 QAQALYPWRAKKDNHLNFNKNDVITVLEQQD--MWWFGEVQGQKGWFPKSYVKL 52

N-terminal (or first) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. The N-terminal SH3 domain increases the affinity of p67phox for the oxidase complex. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212804 Cd Length: 54 Bit Score: 33.72 E-value: 6.51e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 23344846   7 HDFSATADDELSFRKTQILKILNMEDDsNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11871   6 YEFVPETKEELQVLPGNIVFVLKKGTD-NWATVVFNGKKGLVPCNFLE 52

Src Homology 3 domain of Ras GTPase-Activating Protein 1; RasGAP, also called Ras p21 protein activator, RASA1, or p120RasGAP, is part of the GAP1 family of GTPase-activating proteins. It is a 120kD cytosolic protein containing an SH3 domain flanked by two SH2 domains at the N-terminal end, a pleckstrin homology (PH) domain, a calcium dependent phospholipid binding domain (CaLB/C2), and a C-terminal catalytic GAP domain. It stimulates the GTPase activity of normal RAS p21. It acts as a positive effector of Ras in tumor cells. It also functions as a regulator downstream of tyrosine receptors such as those of PDGF, EGF, ephrin, and insulin, among others. The SH3 domain of RasGAP is unable to bind proline-rich sequences but have been shown to interact with protein partners such as the G3BP protein, Aurora kinases, and the Calpain small subunit 1. The RasGAP SH3 domain is necessary for the downstream signaling of Ras and it also influences Rho-mediated cytoskeletal reorganization. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212722 Cd Length: 59 Bit Score: 33.89 E-value: 7.41e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 23344846  15 DELSFRKTQILKILN-MEDDSNWYRAELDGKEGLIPSNYIE 54
Cdd:cd11788  17 DELSFQKGDIFVVHNeLEDGWLWVTSLRTGESGLVFRDLVE 57

Src homology 3 domain of Srms Protein Tyrosine Kinase; Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (Srms) is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Srms lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212780 Cd Length: 55 Bit Score: 33.60 E-value: 7.70e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITV-TDRSDENWWNGEIGN-RKGIFPATYV 206
Cdd:cd11846   1 LFTALYDFTARSTHELSVEQGDKLCViEEEGDYIFARKLTGNpESGLVPASYV 53

Src Homology 3 domain of Bridging integrator 1 (Bin1), also called Amphiphysin-2; Bin1 isoforms are localized in many different tissues and may function in intracellular vesicle trafficking. It plays a role in the organization and maintenance of the T-tubule network in skeletal muscle. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Bin1 contains an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR) and a C-terminal SH3 domain. The SH3 domain of Bin1 forms transient complexes with actin, myosin filaments, and CDK5, to facilitate sarcomere organization and myofiber maturation. It also binds dynamin and prevents its self-assembly. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213015 Cd Length: 72 Bit Score: 34.12 E-value: 8.13e-03

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 23344846 157 VQALYDFVPQESGELDFRRGDVITVT-----DRSDENWWNG----------EIGNRKGIFPATY 205
Cdd:cd12139   5 VQAQHDYTATDTDELQLKAGDVVLVIpfqnpEEQDEGWLMGvkesdwnqhkKLEKCRGVFPENF 68

Src Homology 3 domain of fungal BOI-like proteins; This subfamily includes the Saccharomyces cerevisiae proteins BOI1 and BOI2, and similar proteins. They contain an N-terminal SH3 domain, a Sterile alpha motif (SAM), and a Pleckstrin homology (PH) domain at the C-terminus. BOI1 and BOI2 interact with the SH3 domain of Bem1p, a protein involved in bud formation. They promote polarized cell growth and participates in the NoCut signaling pathway, which is involved in the control of cytokinesis. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212819 Cd Length: 55 Bit Score: 33.46 E-value: 8.30e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 23344846 156 LVQALYDFVPQESGELDFRRGDVITVTDRSDE---NWWNGE--IGNRKGIFPATY 205
Cdd:cd11886   1 LLIVIHDFNARSEDELTLKPGDKIELIEDDEEfgdGWYLGRnlRTGETGLFPVVF 55

Src Homology 3 domain of Calcium/calmodulin-dependent Serine protein Kinase; CASK is a scaffolding protein that is highly expressed in the mammalian nervous system and plays roles in synaptic protein targeting, neural development, and gene expression regulation. CASK interacts with many different binding partners including parkin, neurexin, syndecans, calcium channel proteins, caskin, among others, to perform specific functions in different subcellular locations. Disruption of the CASK gene in mice results in neonatal lethality while mutations in the human gene have been associated with X-linked mental retardation. Drosophila CASK is associated with both pre- and postsynaptic membranes and is crucial in synaptic transmission and vesicle cycling. CASK contains an N-terminal calmodulin-dependent kinase (CaMK)-like domain, two L27 domains, followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213014 Cd Length: 62 Bit Score: 33.72 E-value: 9.37e-03

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 23344846 162 DFVPQESGELDFRRGDVITVTDRSDENWWNGEIGNRKG 199
Cdd:cd12081  14 DLIPCKQAGIRFRVGDILQIISKDDHNWWQAKLENSKN 51

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1; SKAP1, also called SKAP55 (Src kinase-associated protein of 55kDa), is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212977 Cd Length: 53 Bit Score: 33.29 E-value: 9.57e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   8 DFSATADDELSFRKTQILKILNMEDDS-NWYRAELDGKEGLIPSNYI 53
Cdd:cd12044   7 DCFGDNPDELSFQRGDLIYILSKEYNMyGWWVGELNGIVGIVPKDYL 53

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212695 [Multi-domain] Cd Length: 57 Bit Score: 33.49 E-value: 9.85e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 23344846   9 FSATADDELSFRKTQILKILNMEDDSNWYRA-ELDGKEGLIPSNYIE 54
Cdd:cd11761  10 YEAQRPDELTITEGEELEVIEDGDGDGWVKArNKSGEVGYVPENYLQ 56