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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2048631758 1020 GIVYALWDYEAQNNDELSFHEGDAITILRRKDENETEWWWARLGDREGYVPKNLLGL 1076
Cdd:cd11954      1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 57

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  444 GKGPPPIPGVGKP------LPPSYgtyPSPGPLGPGSTSSLERrkegslprPAAGPPSRQKPAPLPPAGSAPQPSSSQQI 517
Cdd:PHA03247  2549 GDPPPPLPPAAPPaapdrsVPPPR---PAPRPSEPAVTSRARR--------PDAPPQSARPRAPVDDRGDPRGPAPPSPL 2617

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  518 QQRISVPPSPTYPPAGPPAFPAgdGKPELPLTVAIRPFLADKGSRPQSPRKgpqtvnsSSIYSMYLQQATPPKNYQPPAH 597
Cdd:PHA03247  2618 PPDTHAPDPPPPSPSPAANEPD--PHPPPTVPPPERPRDDPAPGRVSRPRR-------ARRLGRAAQASSPPQRPRRRAA 2688

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  598 GTLNKSVkAVYGKPVLPSGSASPSP------LPFLHGSLGTGTTQPQPPSECAEKeAEPEGPSVPGEGSTVESLPRPLSP 671
Cdd:PHA03247  2689 RPTVGSL-TSLADPPPPPPTPEPAPhalvsaTPLPPGPAAARQASPALPAAPAPP-AVPAGPATPGGPARPARPPTTAGP 2766

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  672 TKLTPI---VHSPLRYQSDADLEALRRKLANAPRPlkkRSSITEPEGPGGPNIQKLLYQR-FNTLAGGMEGTPFYQPSPS 747
Cdd:PHA03247  2767 PAPAPPaapAAGPPRRLTRPAVASLSESRESLPSP---WDPADPPAAVLAPAAALPPAASpAGPLPPPTSAQPTAPPPPP 2843

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  748 QDFVGTLAdvDNGNTNANGNLDESFPPRPTAPLPdelAPSSDANDNELPSPEPEEliCPQTTHQTAEPTEDNNNNVATVP 827
Cdd:PHA03247  2844 GPPPPSLP--LGGSVAPGGDVRRRPPSRSPAAKP---AAPARPPVRRLARPAVSR--STESFALPPDQPERPPQPQAPPP 2916

                          410       420       430
                   ....*....|....*....|....*....|...
gi 2048631758  828 STEQIPSPVAEAPSEEDQVPPAPLSPVvhPPTA 860
Cdd:PHA03247  2917 PQPQPQPPPPPQPQPPPPPPPRPQPPL--APTT 2947

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2048631758 1020 GIVYALWDYEAQNNDELSFHEGDAITILRRKDENETEWWWARLGDREGYVPKNLLGL 1076
Cdd:cd11954      1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 57

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  889 LLLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHLC 968
Cdd:COG0666    123 PLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIV 202

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  969 KQLVESGAAIFASTiSDIETAADKCEEMeeGYIQCSQFLYGVQEKLGVMNKGIVYALWDYEAQNNDELSFHEGDAITILR 1048
Cdd:COG0666    203 KLLLEAGADVNAKD-NDGKTALDLAAEN--GNLEIVKLLLEAGADLNAKDKDGLTALLLAAAAGAALIVKLLLLALLLLA 279

                   ....*...
gi 2048631758 1049 RKDENETE 1056
Cdd:COG0666    280 AALLDLLT 287

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  444 GKGPPPIPGVGKP------LPPSYgtyPSPGPLGPGSTSSLERrkegslprPAAGPPSRQKPAPLPPAGSAPQPSSSQQI 517
Cdd:PHA03247  2549 GDPPPPLPPAAPPaapdrsVPPPR---PAPRPSEPAVTSRARR--------PDAPPQSARPRAPVDDRGDPRGPAPPSPL 2617

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  518 QQRISVPPSPTYPPAGPPAFPAgdGKPELPLTVAIRPFLADKGSRPQSPRKgpqtvnsSSIYSMYLQQATPPKNYQPPAH 597
Cdd:PHA03247  2618 PPDTHAPDPPPPSPSPAANEPD--PHPPPTVPPPERPRDDPAPGRVSRPRR-------ARRLGRAAQASSPPQRPRRRAA 2688

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  598 GTLNKSVkAVYGKPVLPSGSASPSP------LPFLHGSLGTGTTQPQPPSECAEKeAEPEGPSVPGEGSTVESLPRPLSP 671
Cdd:PHA03247  2689 RPTVGSL-TSLADPPPPPPTPEPAPhalvsaTPLPPGPAAARQASPALPAAPAPP-AVPAGPATPGGPARPARPPTTAGP 2766

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  672 TKLTPI---VHSPLRYQSDADLEALRRKLANAPRPlkkRSSITEPEGPGGPNIQKLLYQR-FNTLAGGMEGTPFYQPSPS 747
Cdd:PHA03247  2767 PAPAPPaapAAGPPRRLTRPAVASLSESRESLPSP---WDPADPPAAVLAPAAALPPAASpAGPLPPPTSAQPTAPPPPP 2843

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  748 QDFVGTLAdvDNGNTNANGNLDESFPPRPTAPLPdelAPSSDANDNELPSPEPEEliCPQTTHQTAEPTEDNNNNVATVP 827
Cdd:PHA03247  2844 GPPPPSLP--LGGSVAPGGDVRRRPPSRSPAAKP---AAPARPPVRRLARPAVSR--STESFALPPDQPERPPQPQAPPP 2916

                          410       420       430
                   ....*....|....*....|....*....|...
gi 2048631758  828 STEQIPSPVAEAPSEEDQVPPAPLSPVvhPPTA 860
Cdd:PHA03247  2917 PQPQPQPPPPPQPQPPPPPPPRPQPPL--APTT 2947

ankyrin repeat protein; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  900 DLVQRIIYEVEDPSKPNDEGITPLHNAV--CAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHL--CKQLVESG 975
Cdd:PHA03100    87 EIVKLLLEYGANVNAPDNNGITPLLYAIskKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKG 166

                   ...
gi 2048631758  976 AAI 978
Cdd:PHA03100   167 VDI 169

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  153 EQRLHFLKQQERRQQQSISENEKLQKLKERVEAQENKLKKiraMRGQVDYSKIMNGNLSAEIERFSAMFQEKKQEVQTAI 232
Cdd:TIGR02168  323 AQLEELESKLDELAEELAELEEKLEELKEELESLEAELEE---LEAELEELESRLEELEEQLETLRSKVAQLELQIASLN 399

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  233 LRVDQLSQQLEDLKKGKLNGFQSYNGRLTGPAAVELKRLYQELqirNQLNQEQNsKLQQQKELLNKRnmeVAMMDKRISE 312
Cdd:TIGR02168  400 NEIERLEARLERLEDRRERLQQEIEELLKKLEEAELKELQAEL---EELEEELE-ELQEELERLEEA---LEELREELEE 472

                          170
                   ....*....|....*..
gi 2048631758  313 LRERLYGKKIQLNRVNG 329
Cdd:TIGR02168  473 AEQALDAAERELAQLQA 489

Centrosomal colon cancer autoantigen protein family; CCCAP is a family of proteins found in eukaryotes. CCCAP is also known as SDCCAG8, serologically defined colon cancer antigen 8. It is associated with the centrosome.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  123 RVELT-----LSELQDMAARQQQQIESQQQMLVAKEQRLHFLKQQERRQQQSISENEKLQKLKERVEAQEnKLKKIRAMR 197
Cdd:pfam15964  494 GLELSeskqrLEQAQQDAARAREECLKLTELLGESEHQLHLTRLEKESIQQSFSNEAKAQALQAQQREQE-LTQKMQQME 572

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  198 GQVD------YSKIMNGN-LSAEIERFSAMFQEKKQEV-QTAILRVDQLSQQLEDLkKGKLNGFQSYNGRLTgPAAVELK 269
Cdd:pfam15964  573 AQHDktvneqYSLLTSQNtFIAKLKEECCTLAKKLEEItQKSRSEVEQLSQEKEYL-QDRLEKLQKRNEELE-EQCVQHG 650

                          170       180       190
                   ....*....|....*....|....*....|..
gi 2048631758  270 RLYQELQIR-NQLNQEQNSKLQQQKELLNKRN 300
Cdd:pfam15964  651 RMHERMKQRlRQLDKHCQATAQQLVQLLSKQN 682

Transient Receptor Potential channel, Vanilloid subfamily (TRPV), types 5 and 6; TRPV5 and TRPV6 (TRPV5/6) are two homologous members within the vanilloid subfamily of the transient receptor potential (TRP) family. TRPV5 and TRPV6 show only 30-40% homology with other members of the TRP family and have unique properties that differentiates them from other TRP channels. They mediate calcium uptake in epithelia and their expression is dramatically increased in numerous types of cancer. The structure of TRPV5/6 shows the typical topology features of all TRP family members, such as six transmembrane regions, a short hydrophobic stretch between transmembrane segments 5 and 6, which is predicted to form the Ca2+ pore, and large intracellular N- and C-terminal domains. The N-terminal domain of TRPV5/6 contains three ankyrin repeats. This structural element is present in several proteins and plays a role in protein-protein interactions. The N- and C-terminal tails of TRPV5/6 each contain an internal PDZ motif which can function as part of a molecular scaffold via interaction with PDZ-domain containing proteins. A major difference between the properties of TRPV5 and TRPV6 is in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues. In contrast, TRPV6 has a broader expression pattern such as expression in the intestine, kidney, placenta, epididymis, exocrine tissues, and a few other tissues.

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 2048631758  922 PLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLH 957
Cdd:cd22192    139 PLSFAACVGNEEIVRLLIEHGADIRAQDSLGNTVLH 174

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 (ASPP) 1 and 2; The ASPP protein (apoptosis-stimulating protein of p53; also called ankyrin repeat-, Src homology 3 domain- and Pro-rich region-containing protein) plays a critical role in regulating apoptosis. The ASPP family consists of three members, ASPP1, ASPP2 and iASPP, all of which bind to p53 and regulate p53-mediated apoptosis. ASPP1 and ASPP2, have a RA domain at their N-terminus and have pro-apoptotic functions, while iASPP is involved in anti-apoptotic responses. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758    4 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGGCHLAEVWRGSERPIPCDHMMYEHLQKWGPRREEVKFFLRHE 83
Cdd:cd16125      1 VILKVYLSDNNQTVTEVPITPETTCQDVVDCCKEPGEENCHLVEVWRGCERPLPEEENPYEILQQWGSHRDEVKFFLRHE 80

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2048631758 1020 GIVYALWDYEAQNNDELSFHEGDAITILRRKDENETEWWWARLGDREGYVPKNLLGL 1076
Cdd:cd11954      1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2048631758 1020 GIVYALWDYEAQNNDELSFHEGDAITILRRKDENETEWWWARLGDREGYVPKNLLGL 1076
Cdd:cd11953      1 GVVYALWDYEGESDDELSFKEGDCMTILRREDEDETEWWWARLNDKEGYVPRNLLGL 57

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  890 LLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFgVNVNAADsDGWTPLHCAASCNSVHLCK 969
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKD-NGRTALHYAARSGHLEIVK 78

                   ....*..
gi 2048631758  970 QLVESGA 976
Cdd:pfam12796   79 LLLEKGA 85

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2048631758  888 ALLLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHL 967
Cdd:COG0666     89 TLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEI 168

                           90
                   ....*....|.
gi 2048631758  968 CKQLVESGAAI 978
Cdd:COG0666    169 VKLLLEAGADV 179

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 2048631758  1019 KGIVYALWDYEAQNNDELSFHEGDAITILRRKDENeteWWWARLGD-REGYVPKN 1072
Cdd:smart00326    2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDG---WWKGRLGRgKEGLFPSN 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2048631758 1022 VYALWDYEAQNNDELSFHEGDAITILRRKD-ENETEWWWARLGDREGYVPKNLLG 1075
Cdd:cd11800      2 YYALYTFEARSPGELSVTEGQVVTVLEKHDlKGNPEWWLVEDRGKQGYVPSNYLA 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        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2048631758 1021 IVYALWDYEAQNNDELSFHEGDAITILRRKDEnetEWWWARLGD--REGYVPKN 1072
Cdd:cd11845      1 IYVALYDYEARTDDDLSFKKGDRLQILDDSDG---DWWLARHLStgKEGYIPSN 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        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2048631758 1021 IVYALWDYEAQNNDELSFHEGDAITILRRkdeNETEWWWARLGDREGYVPKNLL 1074
Cdd:cd11856      1 SYVAIADYEAQGDDEISLQEGEVVEVLEK---NDSGWWYVRKGDKEGWVPASYL 51

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.

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gi 2048631758 1024 ALWDYEAQNNDELSFHEGDAITILRrkdENETEWWWARLGDREGYVPKN 1072
Cdd:cd11827      4 ALYAYDAQDTDELSFNEGDIIEILK---EDPSGWWTGRLRGKEGLFPGN 49

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.

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gi 2048631758 1024 ALWDYEAQNNDELSFHEGDAITILRRKDEnetEWWWARL-GDREGYVP 1070
Cdd:pfam00018    2 ALYDYTAQEPDELSFKKGDIIIVLEKSED---GWWKGRNkGGKEGLIP 46

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.

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gi 2048631758 1021 IVYALWDYEAQNNDELSFHEGDAITILRRkdeNETEWWWARLGDREGYVPKNLLG 1075
Cdd:cd11806      1 EYVAIADFVATDDSQLSFESGDKLLVLRK---PSVDWWWAEHNGCCGYIPASHLH 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.

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gi 2048631758 1022 VYALWDYEAQNNDELSFHEGDAITILRRKDENeteWWWARLGD-REGYVPKN 1072
Cdd:cd11812      2 VVALYDYTANRSDELTIHRGDIIRVLYKDNDN---WWFGSLVNgQQGYFPAN 50

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.

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gi 2048631758 1022 VYALWDYEAQNNDELSFHEGDAITILRRKDEnetEWWWARLGDREGYVPKN 1072
Cdd:cd11840      2 VIALFPYTAQNEDELSFQKGDIINVLSKDDP---DWWRGELNGQTGLFPSN 49

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.

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gi 2048631758 1024 ALWDYEAQNNDELSFHEGDAITILrrkDENETEWWWARLGDREGYVPKNLLGL 1076
Cdd:cd11974      5 ALWDHVTMDDQELAFKAGDVIRVL---EASNKDWWWGRNEDREAWFPASFVRL 54

ankyrin repeat protein; Provisional

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gi 2048631758  900 DLVQRIIYEVEDPSKPNDEGITPLHNAV--CAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHL--CKQLVESG 975
Cdd:PHA03100    87 EIVKLLLEYGANVNAPDNNGITPLLYAIskKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKG 166

                   ...
gi 2048631758  976 AAI 978
Cdd:PHA03100   167 VDI 169

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.

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gi 2048631758 1024 ALWDYEAQNNDELSFHEGDAITILrRKDENETEWWWARLGDREGYVPKN 1072
Cdd:cd11875      4 VLFDYEAENEDELTLREGDIVTIL-SKDCEDKGWWKGELNGKRGVFPDN 51