Crk-Associated Substrate C-terminal domain; This is a C-terminal domain found in CAS family members. The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain pfam00018 and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII presumed domain is functionally uncharacterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 746 ETTEEGWMEDYDYVHLQGKEEFEKNQRQLLEKGS--------IKQNKTQLEQQQlkqferleQEVSRPINnDISGWTPPS 817
Cdd:pfam12026   1 ENEGKSWMEDYDYVHLQGKEEFERQQKELLEKLPaeeqfenlIKQSKSQLEQQQ--------QEVTQPVE-DPSNWTPPQ 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 818 hypqtqrSKLCMGDRQLLLFYMEQCEANITTLTNAIDAFYSSINNNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKSP 897
Cdd:pfam12026  72 -------SQLSPNDRQLLLFYSEQCETHFGALLNAIDAFFSSLSNNQPPKIFVAHSKFVILSAHKLVFIGDTLCRQASAA 144

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1207135133 898 EVRTRVAQHSNTLCDKLKDIVVSTKTAALQYPSPGSTRDMTERVRELAGCTQQFRMAL 955
Cdd:pfam12026 145 DVRNRVLHCSNALCELLKTLVLATKKAALQYPSPAAVQEMVDRVTELSHHAQQFKTVL 202

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  46 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRLKILVGMYDKQ 112
Cdd:cd12001     1 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLDGWWLCSLHGRQGIVPGNRLKILVGMYDKK 67

Crk-Associated Substrate C-terminal domain; This is a C-terminal domain found in CAS family members. The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain pfam00018 and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII presumed domain is functionally uncharacterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 746 ETTEEGWMEDYDYVHLQGKEEFEKNQRQLLEKGS--------IKQNKTQLEQQQlkqferleQEVSRPINnDISGWTPPS 817
Cdd:pfam12026   1 ENEGKSWMEDYDYVHLQGKEEFERQQKELLEKLPaeeqfenlIKQSKSQLEQQQ--------QEVTQPVE-DPSNWTPPQ 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 818 hypqtqrSKLCMGDRQLLLFYMEQCEANITTLTNAIDAFYSSINNNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKSP 897
Cdd:pfam12026  72 -------SQLSPNDRQLLLFYSEQCETHFGALLNAIDAFFSSLSNNQPPKIFVAHSKFVILSAHKLVFIGDTLCRQASAA 144

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1207135133 898 EVRTRVAQHSNTLCDKLKDIVVSTKTAALQYPSPGSTRDMTERVRELAGCTQQFRMAL 955
Cdd:pfam12026 145 DVRNRVLHCSNALCELLKTLVLATKKAALQYPSPAAVQEMVDRVTELSHHAQQFKTVL 202

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding protein, Breast Cancer Anti-estrogen Resistance 1; a protein interaction module; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1 has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 530 LDLDQAMERLSRHQQAVESSVSLLMSFISGNWRSSTQMESNLPAIRQAVDRIRVAVRDLLEFARGAVANATQATDRTLQT 609
Cdd:cd11552     1 LDLEAAMETLARLQQGVSSSVSHLMSFIGGNWRSPEHMEANVQDIHAAVEGVHGAVRELLEFARGAVSNAAQASDRTLHA 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133 610 KLGKQVQKMEEAFQGLVRYSQALDTLGWSPAALmtSQPGTGGDDLDRLIMCARGVPDDTKQLASFLHGNASLLFKRT 686
Cdd:cd11552    81 KLSRQLQKMEEVYQTLVRHSQALDACRWSPAAL--AAPGPTLDDLDRLVMYSRGVPDDAKQLASFLHGNASLLFRRT 155

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  46 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRLKILVGMYDKQ 112
Cdd:cd12001     1 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLDGWWLCSLHGRQGIVPGNRLKILVGMYDKK 67

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 1207135133  51 KALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLH-GRQGIVP 98
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKSE---DGWWKGRNKgGKEGLIP 46

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 124 PSPTQSLINLPQSAYNKIPPAAQYTAMHPAFTPSGSAN--STNPDGVYMLP---PSHGSSLYQVPsgPPTPQPQPKAPAL 198
Cdd:pfam03154 189 PGTTQAATAGPTPSAPSVPPQGSPATSQPPNQTQSTAAphTLIQQTPTLHPqrlPSPHPPLQPMT--QPPPPSQVSPQPL 266

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 199 AKKQTHVQYPPTTQDVYQVPPSINAPG----------QDIYQVPPAAGGQCPG--QDVYQVPPSVNQTQDvyQIPPSLDR 266
Cdd:pfam03154 267 PQPSLHGQMPPMPHSLQTGPSHMQHPVppqpfpltpqSSQSQVPPGPSPAAPGqsQQRIHTPPSQSQLQS--QQPPREQP 344

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 267 SWDSPKPMGKVVVP--TRVGQVYVYDTGKNEQ-----DEYDVPRHLPPSQDIYDVPPTRTQYIQQVYDTPPMAMkgpPSG 339
Cdd:pfam03154 345 LPPAPLSMPHIKPPptTPIPQLPNPQSHKHPPhlsgpSPFQMNSNLPPPPALKPLSSLSTHHPPSAHPPPLQLM---PQS 421

                         250       260       270
                  ....*....|....*....|....*....|....*....
gi 1207135133 340 QEIYDT---PPSVDKSQLHYQQTVYDIPPSVSKDVPDGP 375
Cdd:pfam03154 422 QQLPPPpaqPPVLTQSQSLPPPAASHPPTSGLHQVPSQS 460

Crk-Associated Substrate C-terminal domain; This is a C-terminal domain found in CAS family members. The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain pfam00018 and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII presumed domain is functionally uncharacterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 746 ETTEEGWMEDYDYVHLQGKEEFEKNQRQLLEKGS--------IKQNKTQLEQQQlkqferleQEVSRPINnDISGWTPPS 817
Cdd:pfam12026   1 ENEGKSWMEDYDYVHLQGKEEFERQQKELLEKLPaeeqfenlIKQSKSQLEQQQ--------QEVTQPVE-DPSNWTPPQ 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 818 hypqtqrSKLCMGDRQLLLFYMEQCEANITTLTNAIDAFYSSINNNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKSP 897
Cdd:pfam12026  72 -------SQLSPNDRQLLLFYSEQCETHFGALLNAIDAFFSSLSNNQPPKIFVAHSKFVILSAHKLVFIGDTLCRQASAA 144

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1207135133 898 EVRTRVAQHSNTLCDKLKDIVVSTKTAALQYPSPGSTRDMTERVRELAGCTQQFRMAL 955
Cdd:pfam12026 145 DVRNRVLHCSNALCELLKTLVLATKKAALQYPSPAAVQEMVDRVTELSHHAQQFKTVL 202

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding protein, Breast Cancer Anti-estrogen Resistance 1; a protein interaction module; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1 has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 530 LDLDQAMERLSRHQQAVESSVSLLMSFISGNWRSSTQMESNLPAIRQAVDRIRVAVRDLLEFARGAVANATQATDRTLQT 609
Cdd:cd11552     1 LDLEAAMETLARLQQGVSSSVSHLMSFIGGNWRSPEHMEANVQDIHAAVEGVHGAVRELLEFARGAVSNAAQASDRTLHA 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133 610 KLGKQVQKMEEAFQGLVRYSQALDTLGWSPAALmtSQPGTGGDDLDRLIMCARGVPDDTKQLASFLHGNASLLFKRT 686
Cdd:cd11552    81 KLSRQLQKMEEVYQTLVRHSQALDACRWSPAAL--AAPGPTLDDLDRLVMYSRGVPDDAKQLASFLHGNASLLFRRT 155

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding proteins; a protein interaction module; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1 has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 530 LDLDQAMERLSRHQQAVESSVSLLMSFISGNWRSSTQMESNLPAIRQAVDRIRVAVRDLLEFARGAVANATQATDRTLQT 609
Cdd:cd11549     1 LDLDAAMEKLVRLQQEVSSSVSNLLSFVSSNWRSRENLEPNIDEIKTAVDRLRTSLHEFLEFARGALANAANASDKNLQL 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1207135133 610 KLGKQVQKMEEAFQGLVRYSQALDTLGWSPAALMTSQPGTGGDDLDRLIMCARGVPDDTKQLASFLHGNASLLFKRTNK 688
Cdd:cd11549    81 KLRRQLQPLEDSHQILSQTSQALDDCNWSLEALVDNSPSNKPDDLDRFVMCARTLPDDAKQLASFIHGNASLLFKRAPT 159

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Neural precursor cell Expressed, Developmentally Down-regulated 9; a protein interaction module; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 831 DRQLLLFYMEQCEANITTLTNAIDAFYSSINNNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKSPEVRTRVAQHSNTL 910
Cdd:cd11570     1 DRQLLGFYADQCETHFISLLNAIDAFFSCVSSGQPPRIFVAHSKFVILSAHKLVFIGDTLTRQVTVQDIRNRVMNSSNQL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1207135133 911 CDKLKDIVVSTKTAALQYPSPGSTRDMTERVRELAGCTQQFRMALNQL 958
Cdd:cd11570    81 CELLKTIVMATKMAALHYPSTAALQEMVDRVTDLSHLAQLFKLSLSQM 128

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Embryonal Fyn-associated Substrate; a protein interaction module; EFS is also called HEFS, CASS3 (CAS scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207135133 830 GDRQLLLFYMEQCEANITTLTNAIDAFYSSINNNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKSPEVRTRVAQHSNT 909
Cdd:cd11571     1 EDSQLLHFYAGQCQSHYSTLLAAVAALLSSTQANQPPRVFVPHGKRLIVAAHKLVFVGDTLGRLASSAPLRARVATAGGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1207135133 910 LCDKLKDIVVSTKTAALQYPSPGSTRDMTERVRELAGCTQQFRMALNQL 958
Cdd:cd11571    81 LCQALKAVVLATKGAALGYPSPPAAQEMAQCVADLSGQALQFTTLLQSL 129

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  46 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRLKILVGMYDKQ 112
Cdd:cd12001     1 LNVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLDGWWLCSLHGRQGIVPGNRLKILVGMYDKK 67

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  49 LAKALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRLKIL 105
Cdd:cd12002     1 MARALYDNVPECAEELAFRKGDILTVIEQNTGGLEGWWLCSLHGRQGIAPGNRLKLL 57

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1207135133  48 VLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRLKIL 105
Cdd:cd12003     1 QLAKALYDNAAESPEELSFRRGDVLMVLKREHGSLPGWWLCSLHGQQGIAPANRLRLL 58

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 1207135133   50 AKALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLH-GRQGIVPGNRLK 103
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSD---DGWWKGRLGrGKEGLFPSNYVE 56

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called RelA-associated inhibitor (RAI), is an oncoprotein that inhibits the apoptotic transactivation potential of p53. It is upregulated in human breast cancers expressing wild-type p53, in acute leukemias regardless of the p53 mutation status, as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTQGlEGWWLCSLHGRQGIVPGN 100
Cdd:cd11952     5 ALWDYSAEFPDELSFKEGDMVTVLRKDGEG-TDWWWASLCGREGYVPRN 52

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1207135133  49 LAKALYDNVAESPDELSFRKGDIMTVLERDTQgleGWWLCSLHGRQGIVPGN 100
Cdd:cd11805     1 RVQALYDFNPQEPGELEFRRGDIITVLDSSDP---DWWKGELRGRVGIFPAN 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 1207135133  49 LAKALYDNVAESPDELSFRKGDIMTVLERDTQGL-EGWWLCSLHGRQ-GIVPGNRLKI 104
Cdd:cd11864     1 VARAEYDFVAESEDELSFRAGDKLRLAPKELQPRvRGWLLATVDGQKiGLVPANYVKI 58

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNrlkiLVGM 108
Cdd:cd11807     5 ALFDYEAENGDELSFREGDELTVLRKGDDDETEWWWARLNDKEGYVPRN----LLGL 57

Variant SH3 domain;

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLHGRQGIVPGNRLK 103
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESE---DGWWEGINTGRTGLVPANYVE 49

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 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTQGlEGWWLCSLHGRQGIVPGN 100
Cdd:cd11875     2 ARVLFDYEAENEDELTLREGDIVTILSKDCED-KGWWKGELNGKRGVFPDN 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 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTQgleGWWLCSLHGRQGIVPGN 100
Cdd:cd11827     2 CKALYAYDAQDTDELSFNEGDIIEILKEDPS---GWWTGRLRGKEGLFPGN 49

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

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                  ....*....|....*....|....*....|....*....|....*....|
gi 1207135133  51 KALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLHGRQGIVPGN 100
Cdd:cd11823     3 KALYSYTANREDELSLQPGDIIEVHEKQD---DGWWLGELNGKKGIFPAT 49

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.

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTQGLEGWWLCSLHGRQGIVPGNRL 102
Cdd:cd11953     5 ALWDYEGESDDELSFKEGDCMTILRREDEDETEWWWARLNDKEGYVPRNLL 55

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

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                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1207135133  49 LAKALYDNVAESPDELSFRKGDIMTVlerdTQGLE-GWWLCSLHGRQGIVPGNRLKI 104
Cdd:cd11877     1 LVRAKFNFEGTNEDELSFDKGDIITV----TQVVEgGWWEGTLNGKTGWFPSNYVKE 53

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

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTQglEGWWLCSLHGRQGIVPGN 100
Cdd:cd11804     2 AVAKHDFKATAEDELSFKKGSILKVLNMEDD--PNWYKAELDGKEGLIPKN 50

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
                  ....*....|....*....|....*....|....*....|....*....|
gi 1207135133  51 KALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLHGRQGIVPGN 100
Cdd:cd11826     3 VALYDYTADKDDELSFQEGDIIYVTKKND---DGWYEGVLNGVTGLFPGN 49

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLHGRQGIVPGN 100
Cdd:cd11818     2 ARALYDFTGENEDELSFKAGDIITELESID---EEWMSGELRGKSGIFPKN 49

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

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1207135133  51 KALYDNVAESPDELSFRKGDIMTVLERDTQGLeGWWLCSLHGRQGIVPGNRLKIL 105
Cdd:cd12057     3 KVLFPYEAQNEDELTIKEGDIVTLISKDCIDA-GWWEGELNGRRGVFPDNFVKLL 56

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1207135133  50 AKALYDNVAESPDELSFRKGDIMTvleRDTQGLEGWWLCSLHGRQGIVPGNRLKI 104
Cdd:cd11873     2 VIVEFDYDAEEPDELTLKVGDIIT---NVKKMEEGWWEGTLNGKRGMFPDNFVKV 53

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTqglEGWWLCSLHGRQGIVPGN 100
Cdd:cd11950     2 VRALYDFEALEDDELGFNSGDVIEVLDSSN---PSWWKGRLHGKLGLFPAN 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
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1207135133  50 AKALYDNVAESPD-ELSFRKGDIMTVLER-DTQGLE-GWWLCSLH-GRQGIVPGNRLKI 104
Cdd:cd11771     2 CRALYDFTPENPEmELSLKKGDIVAVLSKtDPLGRDsEWWKGRTRdGRIGWFPSNYVEV 60

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTQgleGWWLCSLHGRQGIVPGN 100
Cdd:cd11840     4 ALFPYTAQNEDELSFQKGDIINVLSKDDP---DWWRGELNGQTGLFPSN 49

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

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1207135133  52 ALYDNVAESPDELSFRKGDIMTVLERDTQ--GLEGWWLCSLHGRQGIVPGN 100
Cdd:cd11876     4 ALFDYDARGEDELTLRRGQPVEVLSKDAAvsGDEGWWTGKIGDKVGIFPSN 54

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

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                  ....*....|....*....|....*....|....*....|....*....|
gi 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLER-DtqglEGWWLCSLHGRQGIVP 98
Cdd:cd11782     2 ARAKYNFNADTGVELSFRKGDVITLTRRvD----ENWYEGRIGGRQGIFP 47

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 1207135133  50 AKALYDNVAESPDELSFRKGDIMTVLERDTQgleGWWLCSLHG--RQGIVPGNRLK 103
Cdd:cd11858     2 YKALYDFAGSVANELSLKKDDIVYIVQKEDN---GWWLAKKLDesKEGWVPAAYLE 54