Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688601837 1095 GMVYALWNYEAQSADELSFQEGDAITVLRRKDDSETDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd11954     1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 57

Exopolysaccharide export protein/domain GumC/Wzc1 [Cell wall/membrane/envelope biogenesis];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  200 YLKQQERRQQQAVSET-----EKLQRLKERVESQEAKLKKIRAMRGQVDYSKVINgNLSAEIEHISGLFQEKQAELQAAV 274
Cdd:COG3206   161 YLEQNLELRREEARKAlefleEQLPELRKELEEAEAALEEFRQKNGLVDLSEEAK-LLLQQLSELESQLAEARAELAEAE 239

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  275 LRVDQLSQQLEdlrrgkmNGLQTLGGQVTGTAALELRKLYQELQ-------------------IRNKLNQEQNSKLQQQK 335
Cdd:COG3206   240 ARLAALRAQLG-------SGPDALPELLQSPVIQQLRAQLAELEaelaelsarytpnhpdviaLRAQIAALRAQLQQEAQ 312

                         170       180       190
                  ....*....|....*....|....*....|...
gi 688601837  336 ELLNKRNMEVTLMDKRINELRDRLYKRKAEARQ 368
Cdd:COG3206   313 RILASLEAELEALQAREASLQAQLAQLEARLAE 345

Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688601837 1095 GMVYALWNYEAQSADELSFQEGDAITVLRRKDDSETDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd11954     1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 57

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837   965 LLDASLEGEFDLVQRIIYEVDNPSTANDEGITPLHNAVCAGHHHIVKFLLDFgVNVNASDsDGWTPLHCAASCNSVHLCK 1044
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKD-NGRTALHYAARSGHLEIVK 78

                   ....*..
gi 688601837  1045 LLVESGA 1051
Cdd:pfam12796   79 LLLEKGA 85

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 688601837  1099 ALWNYEAQSADELSFQEGDAITVLRRKDDsetDWWWSKLN-DKEGYVP 1145
Cdd:pfam00018    2 ALYDYTAQEPDELSFKKGDIIIVLEKSED---GWWKGRNKgGKEGLIP 46

Exopolysaccharide export protein/domain GumC/Wzc1 [Cell wall/membrane/envelope biogenesis];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  200 YLKQQERRQQQAVSET-----EKLQRLKERVESQEAKLKKIRAMRGQVDYSKVINgNLSAEIEHISGLFQEKQAELQAAV 274
Cdd:COG3206   161 YLEQNLELRREEARKAlefleEQLPELRKELEEAEAALEEFRQKNGLVDLSEEAK-LLLQQLSELESQLAEARAELAEAE 239

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  275 LRVDQLSQQLEdlrrgkmNGLQTLGGQVTGTAALELRKLYQELQ-------------------IRNKLNQEQNSKLQQQK 335
Cdd:COG3206   240 ARLAALRAQLG-------SGPDALPELLQSPVIQQLRAQLAELEaelaelsarytpnhpdviaLRAQIAALRAQLQQEAQ 312

                         170       180       190
                  ....*....|....*....|....*....|...
gi 688601837  336 ELLNKRNMEVTLMDKRINELRDRLYKRKAEARQ 368
Cdd:COG3206   313 RILASLEAELEALQAREASLQAQLAQLEARLAE 345

ankyrin repeats; Ankyrin repeats are about 33 amino acids long and occur in at least four consecutive copies. They are involved in protein-protein interactions. The core of the repeat seems to be an helix-loop-helix structure.

                            10        20        30
                    ....*....|....*....|....*....|
gi 688601837    993 EGITPLHNAVCAGHHHIVKFLLDFGVNVNA 1022
Cdd:smart00248    1 DGRTPLHLAAENGNLEVVKLLLDKGADINA 30

DNA double-strand break repair ATPase Rad50;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  202 KQQERRQQQAVSETEKLQRLKERVESQEAKLKKIRAMRGQV------------------DYSKVIN------GNLSAEIE 257
Cdd:PRK03918  245 KELESLEGSKRKLEEKIRELEERIEELKKEIEELEEKVKELkelkekaeeyiklsefyeEYLDELReiekrlSRLEEEIN 324

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  258 HIsglfQEKQAELQAAVLRVDQLSQQLEDLRRGKMnglqtlggqvtgtaALELR-KLYQEL--------QIRNKLNQEQN 328
Cdd:PRK03918  325 GI----EERIKELEEKEERLEELKKKLKELEKRLE--------------ELEERhELYEEAkakkeeleRLKKRLTGLTP 386

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 688601837  329 SKLQQQKELLNKRNMEVTLMDKRINELRDRLYKRKAEAR 367
Cdd:PRK03918  387 EKLEKELEELEKAKEEIEEEISKITARIGELKKEIKELK 425

transient-receptor-potential calcium channel protein; The Transient Receptor Potential Ca2+ Channel (TRP-CC) Family (TC. 1.A.4)The TRP-CC family has also been called the store-operated calcium channel (SOC) family. The prototypical members include the Drosophila retinal proteinsTRP and TRPL (Montell and Rubin, 1989; Hardie and Minke, 1993). SOC members of the family mediate the entry of extracellular Ca2+ into cells in responseto depletion of intracellular Ca2+ stores (Clapham, 1996) and agonist stimulated production of inositol-1,4,5 trisphosphate (IP3). One member of the TRP-CCfamily, mammalian Htrp3, has been shown to form a tight complex with the IP3 receptor (TC #1.A.3.2.1). This interaction is apparently required for IP3 tostimulate Ca2+ release via Htrp3. The vanilloid receptor subtype 1 (VR1), which is the receptor for capsaicin (the ?hot? ingredient in chili peppers) and servesas a heat-activated ion channel in the pain pathway (Caterina et al., 1997), is also a member of this family. The stretch-inhibitable non-selective cation channel(SIC) is identical to the vanilloid receptor throughout all of its first 700 residues, but it exhibits a different sequence in its last 100 residues. VR1 and SICtransport monovalent cations as well as Ca2+. VR1 is about 10x more permeable to Ca2+ than to monovalent ions. Ca2+ overload probably causes cell deathafter chronic exposure to capsaicin. (McCleskey and Gold, 1999). [Transport and binding proteins, Cations and iron carrying compounds]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837   963 ALLLDASLEgEFDLVQRII-------YEVDNPSTANDE-------GITPLHNAVCAGHHHIVKFLLDFGVNVNA------ 1022
Cdd:TIGR00870   84 TLLHAISLE-YVDAVEAILlhllaafRKSGPLELANDQytseftpGITALHLAAHRQNYEIVKLLLERGASVPAracgdf 162

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  1023 ----SDSD----GWTPLHCAASCNSVHLCKLLVESGAAIFAT--------TISDVEtaADKCEEMEEGYIQCSQFLYGVQ 1086
Cdd:TIGR00870  163 fvksQGVDsfyhGESPLNAAACLGSPSIVALLSEDPADILTAdslgntllHLLVME--NEFKAEYEELSCQMYNFALSLL 240

                   ...
gi 688601837  1087 EKL 1089
Cdd:TIGR00870  241 DKL 243

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837   48 MILTVYLSDGEQALTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERAIPFDHMMYEHLQKWGPRKQEVKFYLRHE 127
Cdd:cd16125     1 VILKVYLSDNNQTVTEVPITPETTCQDVVDCCKEPGEENCHLVEVWRGCERPLPEEENPYEILQQWGSHRDEVKFFLRHE 80

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 2 (ASPP2); ASPP2, also termed Bcl2-binding protein (Bbp), or renal carcinoma antigen NY-REN-51, or tumor suppressor p53-binding protein 2 (53BP2), or p53-binding protein 2 (p53BP2), is a member of ASPP protein family and it functions as a tumor suppressor. ASPP2 binds to p53 and enhances p53-mediated transcription of proapoptotic genes. ASSP2 contains a RA domain at the N-terminus. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumor suppression to being oncoproteins. All p53 amino acids that are important for ASPP2 binding are mutated in human cancer, and ASPP2 is frequently downregulated in these tumor cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837   48 MILTVYLSDGEQALTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERAIPFDHMMYEHLQKWGPRKQEVKFYLRHE 127
Cdd:cd17225     1 MFLTVYLSNNEQHFTEVPITPETTCRDVVELCKEPGETDCHLAEVWRGSERPVADNERMLDVLQQWGAQRNEVRFFLRHE 80

Src Homology 3 (SH3) domain of Apoptosis Stimulating of p53 protein 2; ASPP2 is the full length form of the previously-identified tumor supressor, p53-binding protein 2 (p53BP2). ASPP2 activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). It plays a central role in regulating apoptosis and cell growth; ASPP2-deficient mice show postnatal death. Downregulated expression of ASPP2 is frequently found in breast tumors, lung cancer, and diffuse large B-cell lymphoma where it is correlated with a poor clinical outcome. ASPP2 contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP2 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688601837 1095 GMVYALWNYEAQSADELSFQEGDAITVLRRKDDSETDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd11953     1 GVVYALWDYEGESDDELSFKEGDCMTILRREDEDETEWWWARLNDKEGYVPRNLLGL 57

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  963 ALLLDASLEGEFDLVQRIIYEVDNPSTANDEGITPLHNAVCAGHHHIVKFLLDFGVNVNASDSDGWTPLHCAASCNSVHL 1042
Cdd:COG0666    89 TLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEI 168

                          90
                  ....*....|.
gi 688601837 1043 CKLLVESGAAI 1053
Cdd:COG0666   169 VKLLLEAGADV 179

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  964 LLLDASLEGEFDLVQRII-YEVDnPSTANDEGITPLHNAVCAGHHHIVKFLLDFGVNVNASDSDGWTPLHCAASCNSVHL 1042
Cdd:COG0666   123 PLHLAAYNGNLEIVKLLLeAGAD-VNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEI 201

                          90       100
                  ....*....|....*....|....
gi 688601837 1043 CKLLVESGAAIFATTiSDVETAAD 1066
Cdd:COG0666   202 VKLLLEAGADVNAKD-NDGKTALD 224

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688601837  964 LLLDASLEGEFDLVQRIIYEVDNPSTANDEGITPLHNAVCAGHHHIVKFLLDFGVNVNASDSDGWTPLHCAASCNSVHLC 1043
Cdd:COG0666   156 PLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIV 235

                          90       100
                  ....*....|....*....|....*..
gi 688601837 1044 KLLVESGAAIFATTISDVETAADKCEE 1070
Cdd:COG0666   236 KLLLEAGADLNAKDKDGLTALLLAAAA 262

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688601837 1097 VYALWNYEAQSADELSFQEGDAITVLRRKDDsetDWWW-SKLNDKEGYVPRN 1147
Cdd:cd00174     2 ARALYDYEAQDDDELSFKKGDIITVLEKDDD---GWWEgELNGGREGLFPAN 50

Ankyrin repeats (many copies);

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 688601837   996 TPLHNAVCAGHHHIVKFLLDFGVNVNASDSDGWTPLHCAASCNSVHLCKLLV 1047
Cdd:pfam13637    3 TALHAAAASGHLELLRLLLEKGADINAVDGNGETALHFAASNGNVEVLKLLL 54

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWW--SKLNDKEGYVPRN 1147
Cdd:cd11845     4 ALYDYEARTDDDLSFKKGDRLQIL---DDSDGDWWLarHLSTGKEGYIPSN 51

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRkddsETDWWWSKLNDK------EGYVPRNLL 1149
Cdd:cd11847     4 ALWDFKARGDEELSFQAGDQFRIAER----SGDWWTALKLDRaggvvaQGFVPNNYL 56

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 688601837  1099 ALWNYEAQSADELSFQEGDAITVLRRKDDsetDWWWSKLN-DKEGYVP 1145
Cdd:pfam00018    2 ALYDYTAQEPDELSFKKGDIIIVLEKSED---GWWKGRNKgGKEGLIP 46

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRKDDSetDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd11948     4 ALYSFQATESDELPFQKGDILKILNMEDDQ--NWYKAELQGREGYIPKNYIKV 54

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. 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 688601837 1096 MVYALWNYEAQSADELSFQEGDAITVLRRKDDSETDWWWS-KLNDKEGYVP 1145
Cdd:cd11762     1 LVRALYDYEAQSDEELSFPEGAIIRILRKDDNGVDDGWWEgEFNGRVGVFP 51

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 688601837  986 NPSTANDEGITPLHNAV--CAGHHHIVKFLLDFGVNVNASDSDGWTPLHCAASCNSVHL--CKLLVESGAAIFATT 1057
Cdd:PHA03100   98 NVNAPDNNGITPLLYAIskKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKGVDINAKN 173

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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688601837 1097 VYALWNYEAQSADELSFQEGDAITVLRRKDdseTDWWWSKLNDKEGYVPRN 1147
Cdd:cd11840     2 VIALFPYTAQNEDELSFQKGDIINVLSKDD---PDWWRGELNGQTGLFPSN 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 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRKDDsetDWWWSKLNDKEGYVPRN 1147
Cdd:cd11823     4 ALYSYTANREDELSLQPGDIIEVHEKQDD---GWWLGELNGKKGIFPAT 49

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

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gi 688601837 1097 VYALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKE-GYVPRN 1147
Cdd:cd11774     2 AKALYDYDKQTEEELSFNEGDTLDVY---DDSDSDWILVGFNGTQfGFVPAN 50

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd11974     5 ALWDHVTMDDQELAFKAGDVIRVL---EASNKDWWWGRNEDREAWFPASFVRL 54

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKEGYVPRNLLGLY 1152
Cdd:cd11975     9 AVWDHVTMANRELAFKAGDVIKVL---DASNKDWWWGQIDDEEGWFPASFVRLW 59

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 688601837 1096 MVYALWNYEAQSADELSFQEGDAITVLrRKDDSETDWWWSKLNDKEGYVPRN 1147
Cdd:cd11875     1 KARVLFDYEAENEDELTLREGDIVTIL-SKDCEDKGWWKGELNGKRGVFPDN 51

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. 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 688601837 1099 ALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKEGYVPRN 1147
Cdd:cd11833     4 ALYKFKPQENEDLEMRPGDKITLL---DDSNEDWWKGKIEDRVGFFPAN 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 688601837 1100 LWNYEAQSADELSFQEGDAITVLrRKDDSETDWWWSKLNDKEGYVPRNLLGL 1151
Cdd:cd12057     5 LFPYEAQNEDELTIKEGDIVTLI-SKDCIDAGWWEGELNGRRGVFPDNFVKL 55

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.

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gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRKDDSETDWWWSKLNDKEGYVPRNLLGLYP 1153
Cdd:cd12003     5 ALYDNAAESPEELSFRRGDVLMVLKREHGSLPGWWLCSLHGQQGIAPANRLRLLP 59

Src homology 3 domain of Slit-Robo GTPase Activating Proteins; Slit-Robo GTPase Activating Proteins (srGAPs) are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. Vertebrates contain three isoforms of srGAPs (srGAP1-3), all of which are expressed during embryonic and early development in the nervous system but with different localization and timing. A fourth member has also been reported (srGAP4, also called ARHGAP4). srGAPs contain an N-terminal F-BAR domain, a Rho GAP 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 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRKDDsetDWWWSKLNDKEGYVP 1145
Cdd:cd11809     4 AQFDYTGRSERELSFKKGDSLTLYRQVSD---DWWRGQLNGQDGLVP 47

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 688601837 1097 VYALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKEGYVPRN 1147
Cdd:cd11820     3 VRALYDFEAAEDNELTFKAGEIITVL---DDSDPNWWKGSNHRGEGLFPAN 50

Second or C-terminal Src homology 3 domain of NADPH oxidase (Nox) Organizing protein 1; Nox Organizing protein 1 (NoxO1) is a critical regulator of enzyme kinetics of the nonphagocytic NADPH oxidase Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Nox1 is expressed in colon, stomach, uterus, prostate, and vascular smooth muscle cells. NoxO1 is involved in targeting activator subunits (such as NoxA1) to Nox1. It is co-localized with Nox1 in the membranes of resting cells and directs the subcellular localization of Nox1. NoxO1 contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), and a C-terminal proline-rich region (PRR). This model characterizes the second SH3 domain (or C-SH3) of NoxO1. The tandem SH3 domains of NoxO1 interact with the PRR of p22phox, which also complexes with Nox1. 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 688601837 1098 YALWNYEAQSADELSFQEGDAITVLRRKDDSetdWWWSKLNDKEGYVPRNLL 1149
Cdd:cd12024     3 YATRAYEAQKEDELSVPAGVVVEVLQKSDNG---WWLIRYNGRAGYVPSMYL 51

First Src homology 3 domain (or SH3A) 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 first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 688601837 1099 ALWNYEAQSADELSFQEGDAITVlRRKDDSETDWWWSKLNDKEGYVPRN 1147
Cdd:cd11836     4 ALYAFEARNPDEISFQPGDIIQV-DESQVAEPGWLAGELKGKTGWFPAN 51

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. 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 688601837 1099 ALWNYEAQSADELSFQEGDAITVLRRKDDSETdWWWSKLNDKEGYVPRNLL 1149
Cdd:cd11866     4 GLWDCSGNEPDELSFKRGDLIYIISKEYDSFG-WWVGELNGKVGLVPKDYL 53

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.

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gi 688601837 1097 VYALWNYEAQSADELSFQEGDAITVLrrkDDSETDWWWSKLNDKEGYVPRN 1147
Cdd:cd11805     2 VQALYDFNPQEPGELEFRRGDIITVL---DSSDPDWWKGELRGRVGIFPAN 49