Guanine nucleotide exchange factor for Ras-like small GTPases;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1301 LLDIDPYTYATQLTVLEHDLYLRITMFECLDRAWGTKYCNMGGSPNITKFIANANTLTNFVSHTIVKQADVKTRSKLTQY 1380
Cdd:smart00147    1 LLLLDPKELAEQLTLLDFELFRKIDPSELLGSVWGKRSKKSPSPLNLEAFIRRFNEVSNWVATEILKQTTPKDRAELLSK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1381 FVTVAQHCKELNNFSSMTAIVSALYSSPIYRLKKTWDLVSTESKDLLKNLNNLMDSKRNFVKYRELLRSVTDVACVPFFG 1460
Cdd:smart00147   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEKLPSKYKKLFEELEELLSPERNYKNYREALSSCNLPPCIPFLG 160

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1461 VYLSDLTFTFVGNPDFLHNstNIINFSKRTKIANIVEEIISFKRFHYKLKRLD-DIQTVIEASLENVPHIEKQYQLSLQV 1539
Cdd:smart00147  161 VLLKDLTFIDEGNPDFLEN--GLVNFEKRRQIAEILREIRQLQSQPYNLRPNRsDIQSLLQQLLDHLDEEEELYQLSLKI 238

                    ....
gi 365764126   1540 EPRS 1543
Cdd:smart00147  239 EPRV 242

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 365764126   62 IVVAAYDFNYpikkdSSSQLLSVQQGETIYILNKNSSGWWDGLVIDDSnGKVNRGWFPQNF 122
Cdd:cd11883     1 VVVALYDFTP-----KSKNQLSFKAGDIIYVLNKDPSGWWDGVIISSS-GKVKRGWFPSNY 55

Guanine nucleotide exchange factor for Ras-like small GTPases;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1301 LLDIDPYTYATQLTVLEHDLYLRITMFECLDRAWGTKYCNMGGSPNITKFIANANTLTNFVSHTIVKQADVKTRSKLTQY 1380
Cdd:smart00147    1 LLLLDPKELAEQLTLLDFELFRKIDPSELLGSVWGKRSKKSPSPLNLEAFIRRFNEVSNWVATEILKQTTPKDRAELLSK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1381 FVTVAQHCKELNNFSSMTAIVSALYSSPIYRLKKTWDLVSTESKDLLKNLNNLMDSKRNFVKYRELLRSVTDVACVPFFG 1460
Cdd:smart00147   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEKLPSKYKKLFEELEELLSPERNYKNYREALSSCNLPPCIPFLG 160

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1461 VYLSDLTFTFVGNPDFLHNstNIINFSKRTKIANIVEEIISFKRFHYKLKRLD-DIQTVIEASLENVPHIEKQYQLSLQV 1539
Cdd:smart00147  161 VLLKDLTFIDEGNPDFLEN--GLVNFEKRRQIAEILREIRQLQSQPYNLRPNRsDIQSLLQQLLDHLDEEEELYQLSLKI 238

                    ....
gi 365764126   1540 EPRS 1543
Cdd:smart00147  239 EPRV 242

RasGEF domain; Guanine nucleotide exchange factor for Ras-like small GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126  1310 ATQLTVLEHDLYLRITMFECLDRAWGTKYCNmGGSPNITKFIANANTLTNFVSHTIVKQADVKTRSKLTQYFVTVAQHCK 1389
Cdd:pfam00617    3 ARQLTLIEFELFRKIKPRELLGSAWSKKDKK-ENSPNIEAMIARFNKLSNWVASEILSEEDLKKRAKVIKKFIKIAEHCR 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126  1390 ELNNFSSMTAIVSALYSSPIYRLKKTWDLVSTESKDLLKNLNNLMDSKRNFVKYRELLRSVTdVACVPFFGVYLSDLTFT 1469
Cdd:pfam00617   82 ELNNFNSLMAILSGLNSSPISRLKKTWELVSKKYKKTLEELEKLMSPSRNFKNYREALSSAS-PPCIPFLGLYLTDLTFI 160

                          170       180
                   ....*....|....*....|
gi 365764126  1470 FVGNPDFLHNstNIINFSKR 1489
Cdd:pfam00617  161 EEGNPDFLEG--GLINFEKR 178

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 365764126   62 IVVAAYDFNYpikkdSSSQLLSVQQGETIYILNKNSSGWWDGLVIDDSnGKVNRGWFPQNF 122
Cdd:cd11883     1 VVVALYDFTP-----KSKNQLSFKAGDIIYVLNKDPSGWWDGVIISSS-GKVKRGWFPSNY 55

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately N-terminal to the RasGef (Cdc25-like) domain. REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126 1125 TKEALIEHLTSHE-LVDAAFNVTMLITFRSILTAREFFYALIYRYNLYPPEGLsydDYNIWIEKKSNPIKCRVVNIMRTF 1203
Cdd:cd06224     1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENL---EYNDWDKKKSKPIRLRVLNVLRTW 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 365764126 1204 LTQYWTR-NYYEPGIPLILNFAKMVVSEK--IPGAEDLLQKINEK 1245
Cdd:cd06224    78 VENYPYDfFDDEELLELLEEFLNRLVQEGalLQELKKLLRKLLKL 122

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 365764126    64 VAAYDFnypikKDSSSQLLSVQQGETIYILNKNSSGWWDGLVIDDsngkvNRGWFP 119
Cdd:pfam00018    1 VALYDY-----TAQEPDELSFKKGDIIIVLEKSEDGWWKGRNKGG-----KEGLIP 46

Guanine nucleotide exchange factor for Ras-like small GTPases;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1301 LLDIDPYTYATQLTVLEHDLYLRITMFECLDRAWGTKYCNMGGSPNITKFIANANTLTNFVSHTIVKQADVKTRSKLTQY 1380
Cdd:smart00147    1 LLLLDPKELAEQLTLLDFELFRKIDPSELLGSVWGKRSKKSPSPLNLEAFIRRFNEVSNWVATEILKQTTPKDRAELLSK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1381 FVTVAQHCKELNNFSSMTAIVSALYSSPIYRLKKTWDLVSTESKDLLKNLNNLMDSKRNFVKYRELLRSVTDVACVPFFG 1460
Cdd:smart00147   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEKLPSKYKKLFEELEELLSPERNYKNYREALSSCNLPPCIPFLG 160

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   1461 VYLSDLTFTFVGNPDFLHNstNIINFSKRTKIANIVEEIISFKRFHYKLKRLD-DIQTVIEASLENVPHIEKQYQLSLQV 1539
Cdd:smart00147  161 VLLKDLTFIDEGNPDFLEN--GLVNFEKRRQIAEILREIRQLQSQPYNLRPNRsDIQSLLQQLLDHLDEEEELYQLSLKI 238

                    ....
gi 365764126   1540 EPRS 1543
Cdd:smart00147  239 EPRV 242

RasGEF domain; Guanine nucleotide exchange factor for Ras-like small GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126  1310 ATQLTVLEHDLYLRITMFECLDRAWGTKYCNmGGSPNITKFIANANTLTNFVSHTIVKQADVKTRSKLTQYFVTVAQHCK 1389
Cdd:pfam00617    3 ARQLTLIEFELFRKIKPRELLGSAWSKKDKK-ENSPNIEAMIARFNKLSNWVASEILSEEDLKKRAKVIKKFIKIAEHCR 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126  1390 ELNNFSSMTAIVSALYSSPIYRLKKTWDLVSTESKDLLKNLNNLMDSKRNFVKYRELLRSVTdVACVPFFGVYLSDLTFT 1469
Cdd:pfam00617   82 ELNNFNSLMAILSGLNSSPISRLKKTWELVSKKYKKTLEELEKLMSPSRNFKNYREALSSAS-PPCIPFLGLYLTDLTFI 160

                          170       180
                   ....*....|....*....|
gi 365764126  1470 FVGNPDFLHNstNIINFSKR 1489
Cdd:pfam00617  161 EEGNPDFLEG--GLINFEKR 178

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 365764126   62 IVVAAYDFNYpikkdSSSQLLSVQQGETIYILNKNSSGWWDGLVIDDSnGKVNRGWFPQNF 122
Cdd:cd11883     1 VVVALYDFTP-----KSKNQLSFKAGDIIYVLNKDPSGWWDGVIISSS-GKVKRGWFPSNY 55

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately N-terminal to the RasGef (Cdc25-like) domain. REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126 1125 TKEALIEHLTSHE-LVDAAFNVTMLITFRSILTAREFFYALIYRYNLYPPEGLsydDYNIWIEKKSNPIKCRVVNIMRTF 1203
Cdd:cd06224     1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENL---EYNDWDKKKSKPIRLRVLNVLRTW 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 365764126 1204 LTQYWTR-NYYEPGIPLILNFAKMVVSEK--IPGAEDLLQKINEK 1245
Cdd:cd06224    78 VENYPYDfFDDEELLELLEEFLNRLVQEGalLQELKKLLRKLLKL 122

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 365764126   62 IVVAAYDFnypikKDSSSQLLSVQQGETIYILNKNSSGWWDGlviddSNGKVNRGWFPQNF 122
Cdd:cd00174     1 YARALYDY-----EAQDDDELSFKKGDIITVLEKDDDGWWEG-----ELNGGREGLFPANY 51

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   63 VVAAYDfnYPIKKDSSsqlLSVQQGETIYILNKNSSGWWDGLviddSNGKVnrGWFPQNF 122
Cdd:cd11826     2 VVALYD--YTADKDDE---LSFQEGDIIYVTKKNDDGWYEGV----LNGVT--GLFPGNY 50

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 365764126   62 IVVAAYDFNypikkDSSSQLLSVQQGETIYILNKNSSGWWDGLViddsNGKVnrGWFPQNFGRPLR 127
Cdd:cd12060     3 VVKARFNFK-----QTNEDELSVCKGDIIYVTRVEEGGWWEGTL----NGKT--GWFPSNYVREIK 57

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 365764126   65 AAYDFNypiKKDSSSqlLSVQQGETIYILNKNS-SGWWDGLVIddsnGKVnrGWFPQNF 122
Cdd:cd11976     4 ARYDFC---ARDRSE--LSLKEGDIIKILNKKGqQGWWRGEIY----GRV--GWFPANY 51

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 365764126   69 FNYPIKKDSSsqlLSVQQGETIYILNKNSSGWWDGLViddsNGKVnrGWFPQNF 122
Cdd:cd11766     6 FNYEAQREDE---LSLRKGDRVLVLEKSSDGWWRGEC----NGQV--GWFPSNY 50

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 365764126   65 AAYDFNypikkDSSSQLLSVQQGETIYILNKNSSGWWdgLVidDSNGKVNRGWFPQNF 122
Cdd:cd11858     4 ALYDFA-----GSVANELSLKKDDIVYIVQKEDNGWW--LA--KKLDESKEGWVPAAY 52

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 365764126   60 IGIVVaaYDFNypikkDSSSQLLSVQQGETIYILN-KNSSGWWdgLVIDDSNGKvnRGWFPQNF 122
Cdd:cd11775     2 RGKVL--YDFD-----AQSDDELTVKEGDVVYILDdKKSKDWW--MVENVSTGK--EGVVPASY 54

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 365764126   65 AAYDFNYPIKKDSSsqlLSVQQGETIYILNKNSSGWWDGlvidDSNGKVnrGWFPQNF 122
Cdd:cd11901     4 AYVKFNYTAEREDE---LSLVKGTKVIVMEKCSDGWWRG----SYNGQV--GWFPSNY 52

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 365764126   63 VVAAYDFNypikKDSSSQLlSVQQGETIYILNKNSSGWWDGLViddsNGKVnrGWFPQNF 122
Cdd:cd11972     5 VVAIYDYT----KDKEDEL-SFQEGAIIYVIKKNDDGWYEGVM----NGVT--GLFPGNY 53

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 365764126   60 IGIVVAAYdfnypikKDSSSQLLSVQQGETIYILNKNSSGWWDGLVidDSNGKVNR-GWFPQNF 122
Cdd:cd11993     5 IAQVIASY-------TATGPEQLTLAPGQLILIRKKNPGGWWEGEL--QARGKKRQiGWFPANY 59

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.

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gi 365764126   65 AAYDFnypikKDSSSQLLSVQQGETIYILNKNS-SGWWDGLvidDSNGKVnrGWFPQNF 122
Cdd:cd11763     4 ALYDF-----DSQPSGELSLRAGEVLTITRQDVgDGWLEGR---NSRGEV--GLFPSSY 52

Fifth (C-terminal) Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the fifth (C-terminal) SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 365764126   85 QQGETIYILNKNSSGWWDGLVIDdsNGKVNRGWFPQNF 122
Cdd:cd12020    18 QEGVSMEVLEKNPNGWWYCQILD--GVKPFKGWVPSNY 53

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

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gi 365764126   82 LSVQQGETIYILNKNSSGWWDGLViddsNGKVnrGWFPQNF 122
Cdd:cd11874    16 LELKVGDTIEVLGEVEEGWWEGKL----NGKV--GVFPSNF 50

Fourth (C-terminal) Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the fourth (C-terminal) SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 365764126   64 VAAYDFnypikkDSSSQLLSVQQGETIYILNKNSSGWWDGLVIddSNGKVNRGWFPQNFGR 124
Cdd:cd12018     3 VAVADF------EGDEDTSSFKEGTVFEVREKNSSGWWFCKVL--SGGPVWEGWIPSNYLR 55

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

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gi 365764126   82 LSVQQGETIYILNKNSSGWWDGLVIDDsnGKvnRGWFPQNF 122
Cdd:cd11793    16 LTLEEGDVVNVLRKMPDGWYEGERLRD--GE--RGWFPSSY 52

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

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gi 365764126   63 VVAAYDFnypikKDSSSQLLSVQQGETIYILNKNSSGWWDGlvidDSNGKVnrGWFPQNFGRP 125
Cdd:cd12046     2 VVALFSY-----EASQPEDLEFQKGDVILVLSKVNEDWLEG----QCKGKI--GIFPSAFVED 53

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 365764126   82 LSVQQGETIYILNKNSSGWWDGLViddsNGKvnRGWFPQNF 122
Cdd:cd11827    16 LSFNEGDIIEILKEDPSGWWTGRL----RGK--EGLFPGNY 50