Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 1 (ASPP1); ASPP1 is a member of the ASPP protein family (Apoptosi-Stimulating Protein of p53) that activates the p53-mediated apoptotic response. ASSP1 functions as a tumor suppressor and coordinates with p53 to protect hematopoietic stem cell (HSC) pool integrity, guarding against hematological malignancies. ASSP1 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540    1 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGSCHLAEVWRGNERPIPFDHMMYEHLQKWGPRREEVKFFLRHE 80
Cdd:cd17224      3 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRHE 82

                   ...
gi 2462539540   81 DSP 83
Cdd:cd17224     83 DSP 85

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  889 LLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFgVNVNAADsDGWTPLHCAASCNSVHLCK 968
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKD-NGRTALHYAARSGHLEIVK 78

                   ....*..
gi 2462539540  969 QLVESGA 975
Cdd:pfam12796   79 LLLEKGA 85

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  155 FLKQQERRQQQSISE-----NEKLQKLKERVEAQENKLKKIRAMRGQVDYSKIMNgNLSAEIERFSAMFQEKKQEVQTAI 229
Cdd:COG3206    161 YLEQNLELRREEARKaleflEEQLPELRKELEEAEAALEEFRQKNGLVDLSEEAK-LLLQQLSELESQLAEARAELAEAE 239

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  230 LRVDQLSQQLEdlkkgklNGFQSYNGKLTGPAAVELKRLYQELQ-------------------IRNQLNQEQNSKLQQQK 290
Cdd:COG3206    240 ARLAALRAQLG-------SGPDALPELLQSPVIQQLRAQLAELEaelaelsarytpnhpdviaLRAQIAALRAQLQQEAQ 312

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 2462539540  291 ELLNKRNMEVAMMDKRISELRERLYGKKIQLNRVNGTS 328
Cdd:COG3206    313 RILASLEAELEALQAREASLQAQLAQLEARLAELPELE 350

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 1 (ASPP1); ASPP1 is a member of the ASPP protein family (Apoptosi-Stimulating Protein of p53) that activates the p53-mediated apoptotic response. ASSP1 functions as a tumor suppressor and coordinates with p53 to protect hematopoietic stem cell (HSC) pool integrity, guarding against hematological malignancies. ASSP1 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540    1 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGSCHLAEVWRGNERPIPFDHMMYEHLQKWGPRREEVKFFLRHE 80
Cdd:cd17224      3 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRHE 82

                   ...
gi 2462539540   81 DSP 83
Cdd:cd17224     83 DSP 85

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  889 LLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFgVNVNAADsDGWTPLHCAASCNSVHLCK 968
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLLEH-ADVNLKD-NGRTALHYAARSGHLEIVK 78

                   ....*..
gi 2462539540  969 QLVESGA 975
Cdd:pfam12796   79 LLLEKGA 85

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 2462539540  1018 KGVAYALWDYEAQNSDELSFHEGDALTILRRKDEsetEWWWARLGD-REGYVPKN 1071
Cdd:smart00326    2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDD---GWWKGRLGRgKEGLFPSN 53

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 2462539540 1023 ALWDYEAQNSDELSFHEGDALTILRRKDEsetEWWWARL-GDREGYVP 1069
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 2462539540  155 FLKQQERRQQQSISE-----NEKLQKLKERVEAQENKLKKIRAMRGQVDYSKIMNgNLSAEIERFSAMFQEKKQEVQTAI 229
Cdd:COG3206    161 YLEQNLELRREEARKaleflEEQLPELRKELEEAEAALEEFRQKNGLVDLSEEAK-LLLQQLSELESQLAEARAELAEAE 239

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  230 LRVDQLSQQLEdlkkgklNGFQSYNGKLTGPAAVELKRLYQELQ-------------------IRNQLNQEQNSKLQQQK 290
Cdd:COG3206    240 ARLAALRAQLG-------SGPDALPELLQSPVIQQLRAQLAELEaelaelsarytpnhpdviaLRAQIAALRAQLQQEAQ 312

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 2462539540  291 ELLNKRNMEVAMMDKRISELRERLYGKKIQLNRVNGTS 328
Cdd:COG3206    313 RILASLEAELEALQAREASLQAQLAQLEARLAELPELE 350

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 2462539540   917 EGITPLHNAVCAGHHHIVKFLLDFGVNVNA 946
Cdd:smart00248    1 DGRTPLHLAAENGNLEVVKLLLDKGADINA 30

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 2462539540  452 GKQLPPSYGTYPSPTPLGPGSTSSLERRKEGSLPRPSAglpSRQRPTLLPATGSTPQPGSSQQIQQRISVPPSPTYPPAG 531
Cdd:pfam03154   43 GRNSPSAASTSSNDSKAESMKKSSKKIKEEAPSPLKSA---KRQREKGASDTEEPERATAKKSKTQEISRPNSPSEGEGE 119

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  532 PPAFPAGDSKpelpltVAIRPFLADKGSRPQSPR-KGPQTVNS---SSIYSMYLQQATPPKNYQ--PAAHSALNKSVKAV 605
Cdd:pfam03154  120 SSDGRSVNDE------GSSDPKDIDQDNRSTSPSiPSPQDNESdsdSSAQQQILQTQPPVLQAQsgAASPPSPPPPGTTQ 193

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  606 YGKPVLPSGSTSPSPLPFLHGSLSTGTPQPQ-PPSESTEKEPEQDGPAAPADGSTVESLPRPLSPTKLTPIVHS------ 678
Cdd:pfam03154  194 AATAGPTPSAPSVPPQGSPATSQPPNQTQSTaAPHTLIQQTPTLHPQRLPSPHPPLQPMTQPPPPSQVSPQPLPqpslhg 273

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  679 ---PLRYQSDADLEALRRKLANAPRPLKKRSSitEPEGPGGPNIQkllyqrfntLAGGMEGTPFYQPSPSQdfmgtladv 755
Cdd:pfam03154  274 qmpPMPHSLQTGPSHMQHPVPPQPFPLTPQSS--QSQVPPGPSPA---------APGQSQQRIHTPPSQSQ--------- 333

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  756 dnGNTNANGNLEELPPAQ---------PTAPLPAEPAPSSDANDNELPSPEPEEL---------ICPQTTHQTAEPAEDN 817
Cdd:pfam03154  334 --LQSQQPPREQPLPPAPlsmphikppPTTPIPQLPNPQSHKHPPHLSGPSPFQMnsnlppppaLKPLSSLSTHHPPSAH 411

                          410       420       430       440
                   ....*....|....*....|....*....|....*....|...
gi 2462539540  818 NNNVATVPTTEQIPSPVAEapSPGEEQVPPAPLPPASHPPATS 860
Cdd:pfam03154  412 PPPLQLMPQSQQLPPPPAQ--PPVLTQSQSLPPPAASHPPTSG 452

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

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 2462539540  921 PLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLH 956
Cdd:cd22192    139 PLSFAACVGNEEIVRLLIEHGADIRAQDSLGNTVLH 174

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 1 (ASPP1); ASPP1 is a member of the ASPP protein family (Apoptosi-Stimulating Protein of p53) that activates the p53-mediated apoptotic response. ASSP1 functions as a tumor suppressor and coordinates with p53 to protect hematopoietic stem cell (HSC) pool integrity, guarding against hematological malignancies. ASSP1 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540    1 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGSCHLAEVWRGNERPIPFDHMMYEHLQKWGPRREEVKFFLRHE 80
Cdd:cd17224      3 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRHE 82

                   ...
gi 2462539540   81 DSP 83
Cdd:cd17224     83 DSP 85

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 2462539540    1 MILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGSCHLAEVWRGNERPIPFDHMMYEHLQKWGPRREEVKFFLRHE 80
Cdd:cd17225      1 MFLTVYLSNNEQHFTEVPITPETTCRDVVELCKEPGETDCHLAEVWRGSERPVADNERMLDVLQQWGAQRNEVRFFLRHE 80

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 2462539540 1019 GVAYALWDYEAQNSDELSFHEGDALTILRRKDESETEWWWARLGDREGYVPKNLLGL 1075
Cdd:cd11807      1 GVVYALFDYEAENGDELSFREGDELTVLRKGDDDETEWWWARLNDKEGYVPRNLLGL 57

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        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2462539540 1019 GVAYALWDYEAQNSDELSFHEGDALTILRRkDESETEWWWARLGDREGYVPKNLLGL 1075
Cdd:cd11952      1 GVVYALWDYSAEFPDELSFKEGDMVTVLRK-DGEGTDWWWASLCGREGYVPRNYFGL 56

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  887 ALLLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHL 966
Cdd:COG0666     89 TLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEI 168

                           90
                   ....*....|.
gi 2462539540  967 CKQLVESGAAI 977
Cdd:COG0666    169 VKLLLEAGADV 179

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  884 NPLALLLDASLEGEFDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNS 963
Cdd:COG0666     53 LGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGN 132

                           90
                   ....*....|....
gi 2462539540  964 VHLCKQLVESGAAI 977
Cdd:COG0666    133 LEIVKLLLEAGADV 146

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 2462539540  1018 KGVAYALWDYEAQNSDELSFHEGDALTILRRKDEsetEWWWARLGD-REGYVPKN 1071
Cdd:smart00326    2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDD---GWWKGRLGRgKEGLFPSN 53

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. 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 2462539540 1023 ALWDYEAQNSDELSFHEGDALTILrrkDESETEWWWARLGDREGYVPKN 1071
Cdd:cd11772      4 ALYDYEAQHPDELSFEEGDLLYIS---DKSDPNWWKATCGGKTGLIPSN 49

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2462539540 1022 YALWDYEAQNSDELSFHEGDALTILRRKDES-ETEWWWARLGDREGYVPKNLLG 1074
Cdd:cd11800      3 YALYTFEARSPGELSVTEGQVVTVLEKHDLKgNPEWWLVEDRGKQGYVPSNYLA 56

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 2462539540 1023 ALWDYEAQNSDELSFHEGDALTILRRkdesETEWWWARLGDR------EGYVPKNLL 1073
Cdd:cd11847      4 ALWDFKARGDEELSFQAGDQFRIAER----SGDWWTALKLDRaggvvaQGFVPNNYL 56

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. 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 2462539540 1021 AYALWDYEAQNSDELSFHEGDALTILrrkDESETEWWWARLGDREGYVP 1069
Cdd:cd11828      2 AEALWDHVTMDPEELGFKAGDVIEVL---DMSDKDWWWGSIRDEEGWFP 47

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.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 2462539540 1023 ALWDYEAQNSDELSFHEGDALTILRrkdESETEWWWARLGDREGYVPKN 1071
Cdd:cd11827      4 ALYAYDAQDTDELSFNEGDIIEILK---EDPSGWWTGRLRGKEGLFPGN 49

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.

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gi 2462539540 1021 AYALWDYEAQNSDELSFHEGDALTILRRKDESetEWWWARLGDREGYVPKNLLGL 1075
Cdd:cd11948      2 AVALYSFQATESDELPFQKGDILKILNMEDDQ--NWYKAELQGREGYIPKNYIKV 54

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. 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 2462539540 1021 AYALWDYEAQNSDELSFHEGDALTILRRKDeSETEWWWARLGDREGYVPKNLL 1073
Cdd:cd11842      2 AVALYDFAGEQPGDLAFQKGDIITILKKSD-SQNDWWTGRIGGREGIFPANYV 53

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 2462539540 1023 ALWDYEAQNSDELSFHEGDALTILRRKDEsetEWWWARLGDREGYVPKNLLG 1074
Cdd:cd11806      4 AIADFVATDDSQLSFESGDKLLVLRKPSV---DWWWAEHNGCCGYIPASHLH 52

Ras-associating (RA) domain found in Ras-association domain family members, RASSF7, RASSF8, RASSF9, and RASSF10; The RASSF family of proteins shares a conserved RalGDS/AF6 Ras association (RA) domain either in the C-terminus (RASSF1-6) or N-terminus (RASSF7-10). RASSF7-10 lacks a conserved SARAH (Salvador/RASSF/Hpo) motif adjacent to the RA domain that is found in members of the RASSF1-6 family. The structural differences between the C-terminus and N-terminus RASSF subgroups have led to the suggestion that they are two distinct families. RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub). Ras proteins are small GTPases that are involved in cellular signal transduction. The N-terminus RASSF proteins are potential Ras effectors that have been linked to key biological processes, including cell death, proliferation, microtubule stability, promoter methylation, vesicle trafficking and response to hypoxia.

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gi 2462539540   19 ITPETTCRDVV-----EFCKEPGEGSCHLAEVWRGNERPIPFDHMMYEHLQKWGPRREEVKFFLRH 79
Cdd:cd16123     16 VTERTTCQDVIyalaqATGQTNDTGRYVLVERWRGIERPLPPRTRILKVWKAWGEEQSNVQFVLRR 81

ankyrin repeat protein; Provisional

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462539540  899 DLVQRIIYEVEDPSKPNDEGITPLHNAV--CAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNSVHL--CKQLVESG 974
Cdd:PHA03100    87 EIVKLLLEYGANVNAPDNNGITPLLYAIskKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKG 166

                   ...
gi 2462539540  975 AAI 977
Cdd:PHA03100   167 VDI 169

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. 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 2462539540 1020 VAYALWDYEAQNSDELSFHEGDALTILRRKDES-ETEWWWARLGDREGYVPKNLLG 1074
Cdd:cd12141      1 VYYAVYTFKARSPNELSVSANQRVRILEFSDLTgNKEWWLAEANGQKGYVPSNYIR 56

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 2462539540 1024 LWDYEAQNSDELSFHEGDALTILrRKDESETEWWWARLGDREGYVPKNLLGL 1075
Cdd:cd12057      5 LFPYEAQNEDELTIKEGDIVTLI-SKDCIDAGWWEGELNGRRGVFPDNFVKL 55

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 2462539540 1020 VAYALWDYEAQNSDELSFHEGDALTILrRKDESETEWWWARLGDREGYVPKN 1071
Cdd:cd11875      1 KARVLFDYEAENEDELTLREGDIVTIL-SKDCEDKGWWKGELNGKRGVFPDN 51

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 2462539540 1020 VAYALWDYEAQNSDELSFHEGDALTILRRKDESETEWWWARLGDREGYVPKNLLGLYP 1077
Cdd:cd12003      2 LAKALYDNAAESPEELSFRRGDVLMVLKREHGSLPGWWLCSLHGQQGIAPANRLRLLP 59

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 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. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. Its N-terminal SH3 domain 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 2462539540 1021 AYALWDYEAQNSDELSFHEGDALTILrrKDESETEWWWARLGDREGYVPKNLL 1073
Cdd:cd11946      3 AIAKYDFKATADDELSFKRGDILKVL--NEECDQNWYKAELNGKDGFIPKNYI 53