Src homology 3 domain of JNK-interacting protein 1; JNK-interacting protein 1 (JIP1) is also called Islet-brain 1 (IB1) or Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1). It is highly expressed in neurons, where it functions as an adaptor linking motor to cargo during axonal transport. It also affects microtubule dynamics in neurons. JIP1 is also found in pancreatic beta-cells, where it is involved in regulating insulin secretion. In addition to a JNK binding domain, JIP1 also contains SH3 and Phosphotyrosine-binding (PTB) domains. Its SH3 domain homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE 533
Cdd:cd11943    1 THRAVFRFVPRHPDELELEVDDPLLVEVQAEDYWYEAYNMRTGARGIFPAYYAIE 55

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  554 FRVKFLGSVQVPYHK-----------GNDVLCAAMQKIATTRRLTVHFNPPSSCVLEISVRGVKIgvkaddaLEAKGNKC 622
Cdd:pfam00640   1 FAVRYLGSVEVPEERapdkntrmqqaREAIRRVKAAKINKIRGLSGETGPGTKVDLFISTDGLKL-------LNPDTQEL 73

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  623 SHFFQLKNISFCGY-HPKNNKYFGFITKHPADHRFACHVFVSEDSTKALAESVGRAFQQF 681
Cdd:pfam00640  74 IHDHPLVSISFCADgDPDLMRYFAYIARDKATNKFACHVFESEDGAQDIAQSIGQAFALA 133

Src homology 3 domain of JNK-interacting protein 1; JNK-interacting protein 1 (JIP1) is also called Islet-brain 1 (IB1) or Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1). It is highly expressed in neurons, where it functions as an adaptor linking motor to cargo during axonal transport. It also affects microtubule dynamics in neurons. JIP1 is also found in pancreatic beta-cells, where it is involved in regulating insulin secretion. In addition to a JNK binding domain, JIP1 also contains SH3 and Phosphotyrosine-binding (PTB) domains. Its SH3 domain homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE 533
Cdd:cd11943    1 THRAVFRFVPRHPDELELEVDDPLLVEVQAEDYWYEAYNMRTGARGIFPAYYAIE 55

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 320461744   477 EQTHRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRtGARGVFPAYY 530
Cdd:smart00326   2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGR-GKEGLFPSNY 54

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 320461744  109 AAQRPGVGPPKAESNQDPAPRSQGQGPGTGSGDTYRPKrPTTLnlFPQVPRSQdtlnnnslgkKHSWQDRVSrSSSPLKT 188
Cdd:pfam03154 321 SQQRIHTPPSQSQLQSQQPPREQPLPPAPLSMPHIKPP-PTTP--IPQLPNPQ----------SHKHPPHLS-GPSPFQM 386

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  189 GEQTPPHEHI----CLSDELPPQGSPVPTQDRGTSTDSPcrrsaatqmAPPSGPP------ATAPGGRGHSHRDRIHYQA 258
Cdd:pfam03154 387 NSNLPPPPALkplsSLSTHHPPSAHPPPLQLMPQSQQLP---------PPPAQPPvltqsqSLPPPAASHPPTSGLHQVP 457

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  259 DVRLEATEEIY------LTPVQRPPDPAEPTSTFMPPTESRMSVSSDPDPAAYSVTAgrphPSISEEDEGFDCLSSPEra 332
Cdd:pfam03154 458 SQSPFPQHPFVpggpppITPPSGPPTSTSSAMPGIQPPSSASVSSSGPVPAAVSCPL----PPVQIKEEALDEAEEPE-- 531

                         250       260
                  ....*....|....*....|
gi 320461744  333 eppgggwrgslgEPPPPPRA 352
Cdd:pfam03154 532 ------------SPPPPPRS 539

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  554 FRVKFLGSVQVPYHK-----------GNDVLCAAMQKIATTRRLTVHFNPPSSCVLEISVRGVKIgvkaddaLEAKGNKC 622
Cdd:pfam00640   1 FAVRYLGSVEVPEERapdkntrmqqaREAIRRVKAAKINKIRGLSGETGPGTKVDLFISTDGLKL-------LNPDTQEL 73

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  623 SHFFQLKNISFCGY-HPKNNKYFGFITKHPADHRFACHVFVSEDSTKALAESVGRAFQQF 681
Cdd:pfam00640  74 IHDHPLVSISFCADgDPDLMRYFAYIARDKATNKFACHVFESEDGAQDIAQSIGQAFALA 133

Src homology 3 domain of JNK-interacting protein 1; JNK-interacting protein 1 (JIP1) is also called Islet-brain 1 (IB1) or Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1). It is highly expressed in neurons, where it functions as an adaptor linking motor to cargo during axonal transport. It also affects microtubule dynamics in neurons. JIP1 is also found in pancreatic beta-cells, where it is involved in regulating insulin secretion. In addition to a JNK binding domain, JIP1 also contains SH3 and Phosphotyrosine-binding (PTB) domains. Its SH3 domain homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE 533
Cdd:cd11943    1 THRAVFRFVPRHPDELELEVDDPLLVEVQAEDYWYEAYNMRTGARGIFPAYYAIE 55

Src homology 3 domain of JNK-interacting protein 2; JNK-interacting protein 2 (JIP2) is also called Mitogen-activated protein kinase 8-interacting protein 2 (MAPK8IP2) or Islet-brain-2 (IB2). It is widely expressed in the brain, where it forms complexes with fibroblast growth factor homologous factors (FHFs), which facilitates activation of the p38delta MAPK. JIP2 is enriched in postsynaptic densities and may play a role in motor and cognitive function. In addition to a JNK binding domain, JIP2 also contains SH3 and Phosphotyrosine-binding (PTB) domains. The SH3 domain of the related protein JIP1 homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE 533
Cdd:cd11942    1 THRAVFRFIPRHEDELELDVDDPLLVEAEEDDYWYRGYNMRTGERGIFPAFYAHE 55

Cell death protein 6 homolog (CED-6/GULP1) Phosphotyrosine-binding (PTB) domain; CED6 (also known as GULP1: engulfment adaptor PTB domain containing 1) is an adaptor protein involved in the specific recognition and engulfment of apoptotic cells. CED6 has been shown to interact with the cytoplasmic tail of another protein involved in the engulfment of apoptotic cells, CED1. CED6 has a C-terminal PTB domain, which can bind to NPXY motifs. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 553 QFRVKFLGSVQVPYHKGNDVLCAAMQKIATTRRLTVHFNPPSSCV-LEISVRGVKIgvkaddaLEAKGNKCSHFFQLKNI 631
Cdd:cd01273   13 AYLVKFLGCTEVEQPKGTEVVKEAIRKLKFARQLKKSEGAKLPKVeLQISIDGVKI-------QDPKTKVIMHQFPLHRI 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 320461744 632 SFCGYHPKNNKYFGFITKHPADHRFACHVFVSEDSTKALAESVGRAFQQFYKQFVE 687
Cdd:cd01273   86 SFCADDKTDKRIFSFIAKDSESEKHLCFVFDSEKLAEEITLTIGQAFDLAYRRFLE 141

Variant SH3 domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 320461744  482 AIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNmrTGARGVFPAYY 530
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESEDGWWEGIN--TGRTGLVPANY 47

Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 554 FRVKFLGSVQVPYHKGNDVLCAAMQKIattRRLTVHFNPPSSCVLEISVRGVKIgVKADdaleakgNK---CSHffQLKN 630
Cdd:cd01274   17 YEAHYLGSTEIKELRGTESTKKAIQKL---KKSTREMKKIPTIILSISYKGVKF-IDAT-------TKnliCEH--EIRN 83

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 631 ISFCGYHPKNNKYFGFITK-HPADHRFaCHVFVSEDSTKAlAE---SVGRAFQQFYKQFV 686
Cdd:cd01274   84 ISCACQDPEDLNTFAYITKdLKTDHHY-CHVFCVLTVDLA-TEiilTLGQAFEVAYQLAL 141

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing proteins, also called TULA (T cell Ubiquitin LigAnd) family of proteins; UBASH3 or TULA proteins are also referred to as Suppressor of T cell receptor Signaling (STS) proteins. They contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. In some vertebrates, there are two TULA family proteins, called UBASH3A (also called TULA or STS-2) and UBASH3B (also called TULA-2 or STS-1), which show partly overlapping as well as distinct functions. UBASH3B is widely expressed while UBASH3A is only found in lymphoid cells. UBASH3A facilitates apoptosis induced in T cells through its interaction with the apoptosis-inducing factor AIF. UBASH3B is an active phosphatase while UBASH3A is not. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVE----LQAEDYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11791    1 VLRVLYPYTPQEEDELELVPGDYIYVSpeelDSSSDGWVEGTSWLTGCSGLLPENY 56

Numb Phosphotyrosine-binding (PTB) domain; Numb is a membrane associated adaptor protein which plays critical roles in cell fate determination. Numb proteins are involved in control of asymmetric cell division and cell fate choice, endocytosis, cell adhesion, cell migration, ubiquitination of specific substrates and a number of signaling pathways (Notch, Hedgehog, p53). Mutations in Numb plays a critical role in disease (cancer). Numb has an N-terminal PTB domain and a C-terminal NumbF domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 554 FRVKFLGSVQVPYHKGNDVLCAAMQKIATTRRltvhfNPPSScVLEISVRGVKI------GVKADDALEakgnkcshffq 627
Cdd:cd01268   17 FPVKYLGCVEVGESRGMQVCEEALKKLKASRK-----KPVRA-VLWVSGDGLRVvdektkGLIVDQTIE----------- 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 628 lkNISFCGYHPKNNKYFGFITKHPADHRFACHVFVS-EDSTKALAESVGRAFQ 679
Cdd:cd01268   80 --KVSFCAPDRNHERAFSYICRDGTTRRWMCHCFLAvKDSGERLSHAVGCAFA 130

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 320461744 481 RAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11780    3 RALYSYTPQNEDELELREGDIVYVMEKCDDGWFVGTSERTGLFGTFPGNY 52

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 320461744 478 QTHRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIEV 534
Cdd:cd11918    2 TPYKAVYQYRPQNEDELELREGDRVDVMQQCDDGWFVGVSRRTQKFGTFPGNYVAPV 58

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 481 RAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYnmRTGARGVFPAYYAIE 533
Cdd:cd12055    3 QVAFSYLPQNEDELELKVGDIIEVVGEVEEGWWEGV--LNGKTGMFPSNFIKE 53

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 482 AIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIEV 534
Cdd:cd11925    5 ALYAYKPQKNDELELRKGEMYRVIEKCQDGWFKGTSLRTGVSGVFPGNYVTPV 57

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 320461744 479 THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11916    3 SYQALYSYAPQNDDELELRDGDIVDVMEKCDDGWFVGTSRRTKQFGTFPGNY 54

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 481 RAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAynMRTGARGVFPAYYAIE 533
Cdd:cd11874    3 KVLFSYTPQNEDELELKVGDTIEVLGEVEEGWWEG--KLNGKVGVFPSNFVKE 53

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 554 FRVKFLGSVQVpyhkgndvlcAAMQKIATTRRLTVH--FNPPSS-----CVLEISVRGVKIGVKADdaleAKGNKCSHFF 626
Cdd:cd13160    3 FTVKYLGRMPA----------RGLWGIKHTRKPLVDalKNLPKGktlpkTKLEVSSDGVKLEELRG----GFGSSKTVFF 68

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 320461744 627 QLKNISFCGYHPKNNKYFGFITK---HPADHRFACHVFVSEdsTKALAE 672
Cdd:cd13160   69 PIHTISYGVQDLVHTRVFSMIVVgeqDSSNHPFECHAFVCD--SRADAR 115

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 478 QTHRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11917    5 EPFQALYNYMPRNEDELELREGDVIDVMEKCDDGWFVGTSRRTKFFGTFPGNY 57

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  176 QDRVSRSSSPLKTGEQtppHEHICLSDELPPQGSPVPTQDRGTSTDSPCRRSAATQMAPPSGPPATAPGGRGHSHRDRIH 255
Cdd:PHA03247  330 EDGAMEVVSPLPRPRQ---HYPLGFPKRRRPTWTPPSSLEDLSAGRHHPKRASLPTRKRRSARHAATPFARGPGGDDQTR 406

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  256 YQADVRLEA-TEEIYLTPVQRPPDPAEPTSTFMPPTESRMSVSSDPDPAAYSVTAGRPHPSISEEdEGFDCLSSPERAEP 334
Cdd:PHA03247  407 PAAPVPASVpTPAPTPVPASAPPPPATPLPSAEPGSDDGPAPPPERQPPAPATEPAPDDPDDATR-KALDALRERRPPEP 485

                         170
                  ....*....|...
gi 320461744  335 PGGGWRGSLGEPP 347
Cdd:PHA03247  486 PGADLAELLGRHP 498

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744 553 QFRVKFLGSVQVPYHKGNDVLCAAMQKIATT--------RRLTvhfnppsscvLEISVRGVKIgvkaddaLEAKGNKCSH 624
Cdd:cd13159    4 TFYLKYLGSTLVEKPKGEGATAEAVKTIIAMakasgkklQKVT----------LTVSPKGIKV-------TDSATNETIL 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 320461744 625 FFQLKNISFCGYHPKNNKYFGFITKHPADHRFACHVFV--SEDSTKALAESVGRAFQ 679
Cdd:cd13159   67 EVSIYRISYCTADANHDKVFAFIATNQDNEKLECHAFLcaKRKMAQAVTLTVAQAFN 123

Src homology 3 domain of Alpha1,6-fucosyltransferase (Fut8); Fut8 catalyzes the alpha1,6-linkage of a fucose residue from a donor substrate to N-linked oligosaccharides on glycoproteins in a process called core fucosylation, which is crucial for growth factor receptor-mediated biological functions. Fut8-deficient mice show severe growth retardation, early death, and a pulmonary emphysema-like phenotype. Fut8 is also implicated to play roles in aging and cancer metastasis. It contains an N-terminal coiled-coil domain, a catalytic domain, and a C-terminal SH3 domain. The SH3 domain of Fut8 is located in the lumen and its role in glycosyl transfer is unclear. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles 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 320461744 480 HRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAY 529
Cdd:cd11792    2 QVAIYPHKPRNHDEIELRVGDIIGVAGNHWDGYSKGRNRRTGKTGLYPSY 51

TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain; The TBC1D1-like members here include TBC1D1, TBC1D4 (also called Akt substrate of 160 kDa or AS160), and pollux (PLX), a calmodulin-binding protein, and are thought to have a role in regulating cell growth and differentiation. These proteins are thought to function as GTPase-activating protein for Rab family protein(s). They may play a role in the cell cycle and differentiation of various tissues. They all contain an N-terminal PTB domain, a calmodulin CBD domain, and a C-terminal TBC domain which is thought to be a GTPase activator protein of Rab-like small GTPases. Recently, TBC1D1 and TBC1D4 were recognized to potentially link the proximal signalling of insulin and/or exercise with GLUT4. TBC1D4 is thought to be involved in contraction-stimulated glucose uptake, but TBC1D4-independent mechanisms (potentially involving TBC1D1) are likely to be essential for most of the contraction's effect. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 320461744 627 QLKNISFCGYHPKNNKYFGFI---TKHPADHRFACHVFVSEDStkALAESVGRAFQQ 680
Cdd:cd01269   87 QFKDISSCSQGIKHVDHFGFIcreSSEGGGFHFVCYVFKCQSE--SVVDEIMLTIKQ 141

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing protein A; UBASH3A is also called Cbl-Interacting Protein 4 (CLIP4), T cell Ubiquitin LigAnd (TULA), or T cell receptor Signaling (STS)-2. It is only found in lymphoid cells and exhibits weak phosphatase activity. UBASH3A facilitates T cell-induced apoptosis through interaction with the apoptosis-inducing factor AIF. It is involved in regulating the level of phosphorylation of the zeta-associated protein (ZAP)-70 tyrosine kinase. TULA proteins contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles 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 320461744 478 QTHRAIFRFVPRHEDELELEVDDPLLV----ELQAEDYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11937    1 QTLRALFQYKPQNIDELMLSPGDYIFVdptqQSEASEGWVIGISHRTGCRGFLPENY 57

Src Homology 3 domain of fungal BOI-like proteins; This subfamily includes the Saccharomyces cerevisiae proteins BOI1 and BOI2, and similar proteins. They contain an N-terminal SH3 domain, a Sterile alpha motif (SAM), and a Pleckstrin homology (PH) domain at the C-terminus. BOI1 and BOI2 interact with the SH3 domain of Bem1p, a protein involved in bud formation. They promote polarized cell growth and participates in the NoCut signaling pathway, which is involved in the control of cytokinesis. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 320461744 481 RAIFRFVPRHEDELELEVDDPL-LVELQAE--DYWYEAYNMRTGARGVFPAYY 530
Cdd:cd11886    3 IVIHDFNARSEDELTLKPGDKIeLIEDDEEfgDGWYLGRNLRTGETGLFPVVF 55

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 320461744  109 AAQRPGVGPPKAESNQDPAPRSQGQGPGTGSGDTYRPKrPTTLnlFPQVPRSQdtlnnnslgkKHSWQDRVSrSSSPLKT 188
Cdd:pfam03154 321 SQQRIHTPPSQSQLQSQQPPREQPLPPAPLSMPHIKPP-PTTP--IPQLPNPQ----------SHKHPPHLS-GPSPFQM 386

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  189 GEQTPPHEHI----CLSDELPPQGSPVPTQDRGTSTDSPcrrsaatqmAPPSGPP------ATAPGGRGHSHRDRIHYQA 258
Cdd:pfam03154 387 NSNLPPPPALkplsSLSTHHPPSAHPPPLQLMPQSQQLP---------PPPAQPPvltqsqSLPPPAASHPPTSGLHQVP 457

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  259 DVRLEATEEIY------LTPVQRPPDPAEPTSTFMPPTESRMSVSSDPDPAAYSVTAgrphPSISEEDEGFDCLSSPEra 332
Cdd:pfam03154 458 SQSPFPQHPFVpggpppITPPSGPPTSTSSAMPGIQPPSSASVSSSGPVPAAVSCPL----PPVQIKEEALDEAEEPE-- 531

                         250       260
                  ....*....|....*....|
gi 320461744  333 eppgggwrgslgEPPPPPRA 352
Cdd:pfam03154 532 ------------SPPPPPRS 539

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  113 PGVGPPKAESNQDPAPRSQGQGPGTGSGDTYRPKRPTTLNLFPQVPRSqdtlnnnSLGKKHSWQDRVSRSSSPLK--TGE 190
Cdd:PHA03247 2614 PSPLPPDTHAPDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRV-------SRPRRARRLGRAAQASSPPQrpRRR 2686

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  191 QTPPH--EHICLSDELPPQGSPVPTQDRGTS-TDSPCRRSAATQMAPPS----GPPATAPGGRGHSHRDRIHYQADVRLE 263
Cdd:PHA03247 2687 AARPTvgSLTSLADPPPPPPTPEPAPHALVSaTPLPPGPAAARQASPALpaapAPPAVPAGPATPGGPARPARPPTTAGP 2766

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320461744  264 ATEEIYLTPVQRPPdPAEPTSTFMPPTESRMSVSSDPDPAAYSVTAGRPHPSISEEdegfdclSSPERAEPPGggwRGSL 343
Cdd:PHA03247 2767 PAPAPPAAPAAGPP-RRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPA-------ASPAGPLPPP---TSAQ 2835

                         250
                  ....*....|....*.
gi 320461744  344 GEPPPPPRASLSSDTS 359
Cdd:PHA03247 2836 PTAPPPPPGPPPPSLP 2851

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 320461744 482 AIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAI 532
Cdd:cd11784    4 ALHSYSAHRPEELELQKGEGVRVLGKFQEGWLRGLSLVTGRVGIFPSNYVS 54