Epidermal growth factor receptor kinase substrate (EPS8)-like Phosphotyrosine-binding (PTB) domain; EPS8 is a regulator of Rac signaling. It consists of a PTB and an SH3 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659  64 QYRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVHAC 143
Cdd:cd01210    4 QYRVEHLATFTLGREEGVQTVEDALRKLKELDAKGRIWSQEMLLQVNDGWVLLLDIETKEELESFPLSSIQECTAVLSTC 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 144 SYDSILALVCKEPTQSKPDLHLFQCDEVKANLISEDIESAISDSKGGK 191
Cdd:cd01210   84 SYNSILLLVVQEPDQPKPEMHLFQCDEVGAELLVEDLQKALSGKRSGR 131

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 409264659 534 YAKSKYDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGDSGFVPNNILDIM 587
Cdd:cd11764    1 YVRVLYDFTARNSKELSVLKGEYLEVLDDSRQWWKVRNSRGQVGYVPHNILEPY 54

Epidermal growth factor receptor kinase substrate (EPS8)-like Phosphotyrosine-binding (PTB) domain; EPS8 is a regulator of Rac signaling. It consists of a PTB and an SH3 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659  64 QYRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVHAC 143
Cdd:cd01210    4 QYRVEHLATFTLGREEGVQTVEDALRKLKELDAKGRIWSQEMLLQVNDGWVLLLDIETKEELESFPLSSIQECTAVLSTC 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 144 SYDSILALVCKEPTQSKPDLHLFQCDEVKANLISEDIESAISDSKGGK 191
Cdd:cd01210   84 SYNSILLLVVQEPDQPKPEMHLFQCDEVGAELLVEDLQKALSGKRSGR 131

SAM domain of EPS8-like subfamily; SAM (sterile alpha motif) domain of EPS8-like subfamily is a putative protein-protein interaction domain. This subfamily includes epidermal growth factor receptor kinase substrate 8 proteins (EPS8) and epidermal growth factor receptor kinase substrate 8-like (EPSL8) 1, 2, 3 proteins with the SAM domain located in the C-terminal effector region. This region is responsible for intracellular protein localization and is involved in small GTPases (such as Rac and Rab5) activation/inhibition. Proteins belonging to this group participate in coordination and integration of multiple signaling pathways; in particular, they play a role in the control of actin dynamics and in receptor endocytosis. They can form complexes with other proteins; for example, in the actin signaling network they interact with SOS1 and E3b1 (Abl1) proteins as well as with CRIB (via SH3 domains) during the actin filament formation, and in the receptor endocytosis their partner is RN-tre protein.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 409264659 719 NITYDSSPEEVKTWLQSKGFNPVTVNSLGVLNGAQLFSLNKDELRSVCP-EGARVFNQITVQKAAL 783
Cdd:cd09540    1 PLTYDSSPEEVKAWLQAKGFSKITVRSLGVLTGAQLFSLNKEELKTVCPeEGARVYSQLTVQKSAL 66

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659    64 QYRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVHac 143
Cdd:smart00462   5 SFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPQKVILSISSRGVKLIDEDTKAVLHEHPLRRISFCAVGPD-- 82

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 409264659   144 sYDSILALVCKEPTQSKPDLHLFQCDEVkANLISEDIESAISDSKGGKQKRRPE 197
Cdd:smart00462  83 -DLDVFGYIARDPGSSRFACHVFRCEKA-AEDIALAIGQAFQLAYELKLKARSE 134

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 409264659   531 PKKYAKSKYDFVARNSSELSVMKDDVLEILDDRRQ-WWKVRNASGDSGFVPNNIL 584
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDgWWKGRLGRGKEGLFPSNYV 55

Epidermal growth factor receptor kinase substrate (EPS8)-like Phosphotyrosine-binding (PTB) domain; EPS8 is a regulator of Rac signaling. It consists of a PTB and an SH3 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659  64 QYRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVHAC 143
Cdd:cd01210    4 QYRVEHLATFTLGREEGVQTVEDALRKLKELDAKGRIWSQEMLLQVNDGWVLLLDIETKEELESFPLSSIQECTAVLSTC 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 144 SYDSILALVCKEPTQSKPDLHLFQCDEVKANLISEDIESAISDSKGGK 191
Cdd:cd01210   84 SYNSILLLVVQEPDQPKPEMHLFQCDEVGAELLVEDLQKALSGKRSGR 131

SAM domain of EPS8-like subfamily; SAM (sterile alpha motif) domain of EPS8-like subfamily is a putative protein-protein interaction domain. This subfamily includes epidermal growth factor receptor kinase substrate 8 proteins (EPS8) and epidermal growth factor receptor kinase substrate 8-like (EPSL8) 1, 2, 3 proteins with the SAM domain located in the C-terminal effector region. This region is responsible for intracellular protein localization and is involved in small GTPases (such as Rac and Rab5) activation/inhibition. Proteins belonging to this group participate in coordination and integration of multiple signaling pathways; in particular, they play a role in the control of actin dynamics and in receptor endocytosis. They can form complexes with other proteins; for example, in the actin signaling network they interact with SOS1 and E3b1 (Abl1) proteins as well as with CRIB (via SH3 domains) during the actin filament formation, and in the receptor endocytosis their partner is RN-tre protein.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 409264659 719 NITYDSSPEEVKTWLQSKGFNPVTVNSLGVLNGAQLFSLNKDELRSVCP-EGARVFNQITVQKAAL 783
Cdd:cd09540    1 PLTYDSSPEEVKAWLQAKGFSKITVRSLGVLTGAQLFSLNKEELKTVCPeEGARVYSQLTVQKSAL 66

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659    64 QYRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVHac 143
Cdd:smart00462   5 SFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPQKVILSISSRGVKLIDEDTKAVLHEHPLRRISFCAVGPD-- 82

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 409264659   144 sYDSILALVCKEPTQSKPDLHLFQCDEVkANLISEDIESAISDSKGGKQKRRPE 197
Cdd:smart00462  83 -DLDVFGYIARDPGSSRFACHVFRCEKA-AEDIALAIGQAFQLAYELKLKARSE 134

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659  65 YRVEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAVVhacS 144
Cdd:cd00934    3 FQVKYLGSVEVGSSRGVDVVEEALKALAAALKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDP---D 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 409264659 145 YDSILALVCKEPTQSKPDLHLFQC-DEVKANLISEDIESA 183
Cdd:cd00934   80 NPNVFAFIAGEEGGSGFRCHVFQCeDEEEAEEILQAIGQA 119

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 409264659   531 PKKYAKSKYDFVARNSSELSVMKDDVLEILDDRRQ-WWKVRNASGDSGFVPNNIL 584
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDgWWKGRLGRGKEGLFPSNYV 55

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 409264659  536 KSKYDFVARNSSELSVMKDDVLEILDD-RRQWWKVRNASGDSGFVP 580
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKsEDGWWKGRNKGGKEGLIP 46

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 409264659 537 SKYDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGDSGFVPNNILD 585
Cdd:cd11900    7 AKFDYVAQQDQELDIKKNERLWLLDDSKSWWRVRNAMNKTGFVPSNYVE 55

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 409264659 537 SKYDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGDSGFVPNNILD 585
Cdd:cd11899    8 AKWDYTAQQDQELDIKKNERLWLLDDSKTWWRVRNAANRTGYVPSNYVE 56

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDRR-QWWKVRN-ASGDSGFVPNN 582
Cdd:cd11845    6 YDYEARTDDDLSFKKGDRLQILDDSDgDWWLARHlSTGKEGYIPSN 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 409264659 534 YAKSKYDFVARNSSELSVMKDDVLEIL--DDRRQWWKVRNASGDSGFVP 580
Cdd:cd11763    1 KVRALYDFDSQPSGELSLRAGEVLTITrqDVGDGWLEGRNSRGEVGLFP 49

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659 534 YAKSKYDFVARNSS-ELSVMKDDVLEIL---DDRRQ---WWKVRNASGDSGFVPNNILDI 586
Cdd:cd11771    1 FCRALYDFTPENPEmELSLKKGDIVAVLsktDPLGRdseWWKGRTRDGRIGWFPSNYVEV 60

First Src homology 3 domain of the RhoGEF kinase, Kalirin; Kalirin, also called Duo, Duet, or TRAD, is a large neuronal dual Rho guanine nucleotide exchange factor (RhoGEF) that activates Rac1, RhoA, and RhoG using two RhoGEF domains. Kalirin exists in many isoforms generated by alternative splicing and the use of multiple promoters; the major isoforms are kalirin-7, -9, and -12, which differ at their C-terminal ends. Kalirin-12, the longest isoform, contains an N-terminal Sec14p domain, spectrin-like repeats, two RhoGEF domains, two SH3 domains, as well as Ig, FNIII, and kinase domains at the C-terminal end. Kalirin-7 contains only a single RhoGEF domain and does not contain an SH3 domain. Kalirin, through its many isoforms, interacts with many different proteins and is able to localize to different locations within the cell. It influences neurite initiation, axon growth, dendritic morphogenesis, vesicle trafficking, neuronal maintenance, and neurodegeneration. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 409264659 540 DFVARNSSELSVMKDDVLEILD---DRRQWWKVR-----NASGDSGFVPNNILDI 586
Cdd:cd11852    8 DFEATSSQELTVSKGQTVEVLErpsSRPDWCLVRtleqdNSPPQEGLVPSSILCI 62

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 409264659 535 AKSKYDFVARNSSELSVMKDDVLEILDDRRQWWKVRnASGDSGFVPNNILDI 586
Cdd:cd11947    2 ARGKFDFTASGEDELSFKKGDVLKILSSDDIWFKAE-LNGEEGYVPKNFVDI 52

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 409264659 535 AKSKYDFVARNSSELSVMKDDVLEIL--DDRRQWWKVRNASGDSGFVPNNILDI 586
Cdd:cd11912    2 AKVLYDYTASGDDEVSISEGEEVTVLepDDGSGWTKVRNGSGEEGLVPTSYIEI 55

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659   67 VEHLTTFVLDRKDAMITVEDGIRKLKLLDAKGKVWT-------QDMILQVDDRAVSLIDLESKNELENFPLNTISHCqAV 139
Cdd:pfam00640   9 VEVPEERAPDKNTRMQQAREAIRRVKAAKINKIRGLsgetgpgTKVDLFISTDGLKLLNPDTQELIHDHPLVSISFC-AD 87

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 409264659  140 VHAcSYDSILALVCKEPTQSKPDLHLFQCDEvKANLISEDIESAIS 185
Cdd:pfam00640  88 GDP-DLMRYFAYIARDKATNKFACHVFESED-GAQDIAQSIGQAFA 131

Low Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1) in mammals and similar proteins Phosphotyrosine-binding (PTB) PH-like fold; The null mutations in the LDL receptor adaptor protein 1 (LDLRAP1) gene, which serves as an adaptor for LDLR endocytosis in the liver, causes autosomal recessive hypercholesterolemia (ARH). LDLRAP1 contains a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd contains mammals, insects, and sponges.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 409264659  64 QYRVEHL-TTFVLDRKDAMITVEDGIRKLKLLDAKGKVWtQDMILQVDDRAVSLIDLESKNELENFPLNTISHCQAvvhA 142
Cdd:cd13159    4 TFYLKYLgSTLVEKPKGEGATAEAVKTIIAMAKASGKKL-QKVTLTVSPKGIKVTDSATNETILEVSIYRISYCTA---D 79

                         90       100
                 ....*....|....*....|....*.
gi 409264659 143 CSYDSILALVCKEPTQSKPDLHLFQC 168
Cdd:cd13159   80 ANHDKVFAFIATNQDNEKLECHAFLC 105

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 409264659 539 YDFVARNSSELSVMKDDVLEILD---DRRQWWKVRNASGDSGFVPNNILDI 586
Cdd:cd11904    7 YPFSSSNDEELNFEKGEVMDVIEkpeNDPEWWKCRKANGQVGLVPKNYVTV 57

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 409264659 534 YAKSKYDFVARNSSELSVMKDDVLEILD-DRRQWWKVRnASGDSGFVPNN 582
Cdd:cd11951    1 FVQAQYDFSAEDPSQLSFRRGDIIEVLDcPDPNWWRGR-ISGRVGFFPRN 49

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 409264659 536 KSKYDFVARNSSELSVMKDDVLEIL---DDRRQWWKVRNASGDSGFVPNNILDIM 587
Cdd:cd11903    4 QTLYPFSSVTEEELNFEKGETMEVIekpENDPEWWKCKNSRGQVGLVPKNYVVVL 58

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 409264659  534 YAKSKYDFVARNSSELSVMKDDVLEILDDRR-QWWKVRNaSGDSGFVPNNIL 584
Cdd:pfam07653   1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDNdGWWEGET-GGRVGLVPSTAV 51

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGD-----SGFVPNNIL 584
Cdd:cd11847    6 WDFKARGDEELSFQAGDQFRIAERSGDWWTALKLDRAggvvaQGFVPNNYL 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 409264659 539 YDFVARNSSELSVMKDDVLEILddRRQ-------WWKVRNaSGDSGFVPNNILD 585
Cdd:cd11800    6 YTFEARSPGELSVTEGQVVTVL--EKHdlkgnpeWWLVED-RGKQGYVPSNYLA 56

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDRR-QWWKVRNASGDSGFVPNNIL 584
Cdd:cd11908    7 YDYQTNDPQELALRYNEEYHLLDSSEiHWWRVQDKNGHEGYVPSSYL 53

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 536 KSKYDFVARNSSELSVMKDDVLEILDDRR-QWWKVRNASGDSGFVPNN 582
Cdd:cd11907    4 KALYDFLPREPSNLALKRAEEYLILEQYDpHWWKARDRYGNEGLIPSN 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 409264659 535 AKSKYDFVARNSSELSVMKDDVLEILD-DRRQWWKVR---NASGDS---GFVPNN 582
Cdd:cd11773    2 YKALYDYEPQTEDELTIQEDDILYLLEkSDDDWWKVKlkvNSSDDDepvGLVPAT 56

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDD-RRQWWKVRNASGDSGFVPNN 582
Cdd:cd11906    7 YDYTPMNAQDLQLRKGEEYVILEEsNLPWWRARDKNGREGYIPSN 51

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 539 YDFVARNSSELSVMKDDVLEILD-DRRQWWKVRNaSGDSGFVPNNILD 585
Cdd:cd11856    6 ADYEAQGDDEISLQEGEVVEVLEkNDSGWWYVRK-GDKEGWVPASYLE 52

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGDSGFVPNN 582
Cdd:cd11837    6 YPWRAKKENHLSFAKGDIITVLEQQEMWWFGELEGGEEGWFPKS 49

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 409264659 535 AKSKYDFVARNSSELSVMKDDVLEILDDRRQ-----WWKVRNASGDSGFVPNN 582
Cdd:cd11864    2 ARAEYDFVAESEDELSFRAGDKLRLAPKELQprvrgWLLATVDGQKIGLVPAN 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 409264659 536 KSKYDFVARNSSELSVMKDDVLEILDDRRQ-WWKVRNASGDSGFVPNNIL 584
Cdd:cd11849    3 RALYDFKSAEPNTLSFSEGETFLLLERSNAhWWLVTNHSGETGYVPANYV 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDR-----RQWWkVRNASGDSGFVPNNIL 584
Cdd:cd12141    6 YTFKARSPNELSVSANQRVRILEFSdltgnKEWW-LAEANGQKGYVPSNYI 55

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 409264659 539 YDFVARNSSELSVMKDDVLEIL--DDRRQWWKVRnASGDSGFVPNNILDI 586
Cdd:cd11948    6 YSFQATESDELPFQKGDILKILnmEDDQNWYKAE-LQGREGYIPKNYIKV 54

Src Homology 3 domain of Sorting Nexin 33; SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX33 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 409264659 535 AKSKYDFVARNSSELSVMKDDVLEILDDRR--QWWKVRNASGDSGFVPNNILDI 586
Cdd:cd11896    2 ARALYSFQSENKEEINIQENEELVIFSENSldGWLQGQNSRGETGLFPASYVEI 55

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 409264659 539 YDFVARNSSELSVMKDDVLEILDDRRQWWKVRNASGD--SGFVPNN 582
Cdd:cd11846    6 YDFTARSTHELSVEQGDKLCVIEEEGDYIFARKLTGNpeSGLVPAS 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 409264659 536 KSKYDFVARNSSELSVMKDDVLEILDDRR-QWWKVRNASGdSGFVPNN 582
Cdd:cd11820    4 RALYDFEAAEDNELTFKAGEIITVLDDSDpNWWKGSNHRG-EGLFPAN 50