first ubiquitin-like (Ubl) domain located at the N-terminus of coronavirus SARS-CoV non-structural protein 3 (Nsp3) and related proteins; This ubiquitin-like (Ubl) domain (Ubl1) is found at the N-terminus of coronavirus Nsp3, a large multi-functional multi-domain protein which is an essential component of the replication/transcription complex (RTC). The functions of Ubl1 in CoVs are related to single-stranded RNA (ssRNA) binding and to interacting with the nucleocapsid (N) protein. SARS-CoV Ubl1 has been shown to bind ssRNA having AUA patterns, and since the 5'-UTR of the SARS-CoV genome has a number of AUA repeats, it may bind there. In mouse hepatitis virus (MHV), this Ubl1 domain binds the cognate N protein. Adjacent to Ubl1 is a Glu-rich acidic region (also referred to as hypervariable region, HVR); Ubl1 together with HVR has been called Nsp3a. Currently, the function of HVR in CoVs is unknown. This model corresponds to one of two Ubl domains in Nsp3; the other is located N-terminal to the papain-like protease (PLpro) and is not represented by this model.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794   38 KTILTVFLSDNQQLLTEVPITPETLCKDVVEFCKEAGESGCHLAEVWKGKERAIPFDQMMFEHLQKWGQRRAEVKFYLRH 117
Cdd:cd17224     2 PMILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRH 81

                  ....
gi 688593794  118 EECP 121
Cdd:cd17224    82 EDSP 85

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  878 LLLDASLEGEFDLVQRIIYEVENPSTPNDEGITPLHNSVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHLC 957
Cdd:COG0666   123 PLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIV 202

                          90       100
                  ....*....|....*....|...
gi 688593794  958 KLLVESGAAIFATTiSDVETAAD 980
Cdd:COG0666   203 KLLLEAGADVNAKD-NDGKTALD 224

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  192 EQRLRYLKQQdpcQGQSASESDKLQRLRERVENQEAKLKKVRAMRGQVDYSKlinGNLSAEIEhvsslFQEKQAELQSAM 271
Cdd:COG4717    77 EEELKEAEEK---EEEYAELQEELEELEEELEELEAELEELREELEKLEKLL---QLLPLYQE-----LEALEAELAELP 145

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  272 LKVDQLTQQLDDLRQgrlnglqplggpvtsnAALELRKLYQEL-QIRNKLNQEQNSKLQQHKDMLNKRNMEVTMMDKRIG 350
Cdd:COG4717   146 ERLEELEERLEELRE----------------LEEELEELEAELaELQEELEELLEQLSLATEEELQDLAEELEELQQRLA 209

                         170
                  ....*....|....*
gi 688593794  351 DLRERLYKKKAELGR 365
Cdd:COG4717   210 ELEEELEEAQEELEE 224

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 688593794   38 KTILTVFLSDNQQLLTEVPITPETLCKDVVEFCKEAGESGCHLAEVWKGKERAIPFDQMMFEHLQKWGQRRAEVKFYLRH 117
Cdd:cd17224     2 PMILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRH 81

                  ....
gi 688593794  118 EECP 121
Cdd:cd17224    82 EDSP 85

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  878 LLLDASLEGEFDLVQRIIYEVENPSTPNDEGITPLHNSVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHLC 957
Cdd:COG0666   123 PLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIV 202

                          90       100
                  ....*....|....*....|...
gi 688593794  958 KLLVESGAAIFATTiSDVETAAD 980
Cdd:COG0666   203 KLLLEAGADVNAKD-NDGKTALD 224

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 688593794   1008 KGTVYALWDYEAQSADELSFREGDALTIMSRRDDsetEWWWAKVND-KEGYVPRN 1061
Cdd:smart00326    2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDD---GWWKGRLGRgKEGLFPSN 53

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  889 DLVQRIIYEVENPSTPNDEGITPLHN--SVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHL--CKLLVESG 964
Cdd:PHA03100   87 EIVKLLLEYGANVNAPDNNGITPLLYaiSKKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKG 166

                  ....*..
gi 688593794  965 AAIFATT 971
Cdd:PHA03100  167 VDINAKN 173

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  192 EQRLRYLKQQdpcQGQSASESDKLQRLRERVENQEAKLKKVRAMRGQVDYSKlinGNLSAEIEhvsslFQEKQAELQSAM 271
Cdd:COG4717    77 EEELKEAEEK---EEEYAELQEELEELEEELEELEAELEELREELEKLEKLL---QLLPLYQE-----LEALEAELAELP 145

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  272 LKVDQLTQQLDDLRQgrlnglqplggpvtsnAALELRKLYQEL-QIRNKLNQEQNSKLQQHKDMLNKRNMEVTMMDKRIG 350
Cdd:COG4717   146 ERLEELEERLEELRE----------------LEEELEELEAELaELQEELEELLEQLSLATEEELQDLAEELEELQQRLA 209

                         170
                  ....*....|....*
gi 688593794  351 DLRERLYKKKAELGR 365
Cdd:COG4717   210 ELEEELEEAQEELEE 224

Domain of unknown function (DUF4659); This family of proteins is found in eukaryotes. Proteins in this family are typically between 427 and 674 amino acids in length. There are two completely conserved residues (D and I) that may be functionally important.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794   182 IAKLSIVR-SEEQRLRYLKQQDPCQGQSASESDKLQRLRERVENQEAKLKKVRAMRGQVDYSKlinGNLSAEiEHVSSLF 260
Cdd:pfam15558    9 IAALMLARhKEEQRMRELQQQAALAWEELRRRDQKRQETLERERRLLLQQSQEQWQAEKEQRK---ARLGRE-ERRRADR 84

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794   261 QEKQAELQSamlkvDQLTQQLDD---LRQGRLNGLQPLGgpvtsnaalELRKLYQELQIRnklnqEQNSKLQQHKDMLNK 337
Cdd:pfam15558   85 REKQVIEKE-----SRWREQAEDqenQRQEKLERARQEA---------EQRKQCQEQRLK-----EKEEELQALREQNSL 145

                          170       180
                   ....*....|....*....|...
gi 688593794   338 RNMEVTMMDKRIGDLRERLYKKK 360
Cdd:pfam15558  146 QLQERLEEACHKRQLKEREEQKK 168

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  528 PPSPTPGSALFPHGERTEPPLAVAVRPFIPDRGSRPQSPRKGPatmnsssiynmylQQPTAKNYSGSSRTAVKAVYGKPV 607
Cdd:PHA03247 2551 PPPPLPPAAPPAAPDRSVPPPRPAPRPSEPAVTSRARRPDAPP-------------QSARPRAPVDDRGDPRGPAPPSPL 2617

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  608 LPGSTSPSPVPLYQQSSTDETDREAAQENHPLPPSSVENIPRPLSPTKLT------PVAHSPLRYQSdidlevlRRKLSN 681
Cdd:PHA03247 2618 PPDTHAPDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRArrlgraAQASSPPQRPR-------RRAARP 2690

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  682 APRPLKKRSSITEPEGPSGPNIQKLLYQRFNTLAGGIESGVGGTPFYQPDSPLNYMATALGNVDTANGNLMESSMLVEPS 761
Cdd:PHA03247 2691 TVGSLTSLADPPPPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPA 2770

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  762 AELVMV--PPPTASVSPTADDNENKLTHLSSDSGGAQSADALEHSLKDTHEDNHNNNHTNVTDTQPSSVPEPHSPAEEDI 839
Cdd:PHA03247 2771 PPAAPAagPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPPTSAQPTAPPPPPGPPPPSL 2850

                  ....*....
gi 688593794  840 TAQSGMSPG 848
Cdd:PHA03247 2851 PLGGSVAPG 2859

DNA double-strand break repair ATPase Rad50;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  181 LIAKLSIVRSEEQRLRYLK--------QQDPCQGQSASESDKLQRLRERVENQEAKLKKVRAMRGQV--------DYSKL 244
Cdd:PRK03918  219 LREELEKLEKEVKELEELKeeieelekELESLEGSKRKLEEKIRELEERIEELKKEIEELEEKVKELkelkekaeEYIKL 298

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  245 IN----------------GNLSAEIEHVsslfQEKQAELQSAMLKVDQLTQQLDDLRQgRLNGLQPlggpvtSNAALE-L 307
Cdd:PRK03918  299 SEfyeeyldelreiekrlSRLEEEINGI----EERIKELEEKEERLEELKKKLKELEK-RLEELEE------RHELYEeA 367

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688593794  308 RKLYQELQ-IRNKLNQEQNSKLQQHKDMLNKRNMEVTMMDKRIGDLRERLYKKKAEL 363
Cdd:PRK03918  368 KAKKEELErLKKRLTGLTPEKLEKELEELEKAKEEIEEEISKITARIGELKKEIKEL 424

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        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  878 LLLDASLEGEFDLVQRIIyevENPSTPNDE----GITPLHNSVCAGHHHIVKFLLDFG---VNvNAADSD---GWTPLHC 947
Cdd:cd22192    20 PLLLAAKENDVQAIKKLL---KCPSCDLFQrgalGETALHVAALYDNLEAAVVLMEAApelVN-EPMTSDlyqGETALHI 95

                          90
                  ....*....|....*...
gi 688593794  948 AASCNNVHLCKLLVESGA 965
Cdd:cd22192    96 AVVNQNLNLVRELIARGA 113

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 688593794   38 KTILTVFLSDNQQLLTEVPITPETLCKDVVEFCKEAGESGCHLAEVWKGKERAIPFDQMMFEHLQKWGQRRAEVKFYLRH 117
Cdd:cd17224     2 PMILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLRH 81

                  ....
gi 688593794  118 EECP 121
Cdd:cd17224    82 EDSP 85

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 688593794 1009 GTVYALWDYEAQSADELSFREGDALTIMSRRDDSETEWWWAKVNDKEGYVPRNLLGL 1065
Cdd:cd11954     1 GMVYALWDYEAQNADELSFQEGDAITILRRKDDSETEWWWARLNDKEGYVPKNLLGL 57

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 688593794 1009 GTVYALWDYEAQSADELSFREGDALTIMSRRDDSETEWWWAKVNDKEGYVPRNLLGL 1065
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 688593794 1009 GTVYALWDYEAQSADELSFREGDALTIMsRRDDSETEWWWAKVNDKEGYVPRNLLGL 1065
Cdd:cd11952     1 GVVYALWDYSAEFPDELSFKEGDMVTVL-RKDGEGTDWWWASLCGREGYVPRNYFGL 56

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  877 ALLLDASLEGEFDLVQRIIYEVENPSTPNDEGITPLHNSVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHL 956
Cdd:COG0666    89 TLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEI 168

                          90
                  ....*....|.
gi 688593794  957 CKLLVESGAAI 967
Cdd:COG0666   169 VKLLLEAGADV 179

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688593794  874 NPLALLLDASLEGEFDLVQRIIYEVENPSTPNDEGITPLHNSVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNN 953
Cdd:COG0666    53 LGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGN 132

                          90
                  ....*....|....
gi 688593794  954 VHLCKLLVESGAAI 967
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 688593794   1008 KGTVYALWDYEAQSADELSFREGDALTIMSRRDDsetEWWWAKVND-KEGYVPRN 1061
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        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688593794 1011 VY-ALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAKVNDKEGYVPRN 1061
Cdd:cd11772     1 VFrALYDYEAQHPDELSFEEGDLLYIS---DKSDPNWWKATCGGKTGLIPSN 49

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 688593794 1010 TVYALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAK--VNDKEGYVPRN 1061
Cdd:cd11845     1 IYVALYDYEARTDDDLSFKKGDRLQIL---DDSDGDWWLARhlSTGKEGYIPSN 51

Ankyrin repeats (many copies);

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 688593794   910 TPLHNSVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHLCKLLV 961
Cdd:pfam13637    3 TALHAAAASGHLELLRLLLEKGADINAVDGNGETALHFAASNGNVEVLKLLL 54

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 688593794 1012 YALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAKVNDKEGYVPRNLL 1063
Cdd:cd11856     3 VAIADYEAQGDDEISLQEGEVVEVL---EKNDSGWWYVRKGDKEGWVPASYL 51

ankyrin repeat protein; Provisional

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gi 688593794  889 DLVQRIIYEVENPSTPNDEGITPLHN--SVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHCAASCNNVHL--CKLLVESG 964
Cdd:PHA03100   87 EIVKLLLEYGANVNAPDNNGITPLLYaiSKKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNKIDLkiLKLLIDKG 166

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gi 688593794  965 AAIFATT 971
Cdd:PHA03100  167 VDINAKN 173

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 688593794 1010 TVYALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAKVNDKE-GYVPRN 1061
Cdd:cd11774     1 QAKALYDYDKQTEEELSFNEGDTLDVY---DDSDSDWILVGFNGTQfGFVPAN 50

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

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gi 688593794 1013 ALWDYEAQSADELSFREGDALTIMSRRDDSetEWWWAKVNDKEGYVPRN 1061
Cdd:cd11804     4 AKHDFKATAEDELSFKKGSILKVLNMEDDP--NWYKAELDGKEGLIPKN 50

C-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. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. 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 688593794 1010 TVYALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAKVNDKEGYVPRN 1061
Cdd:cd11949     1 YVQALFDFDPQEDGELGFRRGDFIEVM---DNSDPNWWKGACHGQTGMFPRN 49

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.

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gi 688593794 1011 VYALWDYEAQSADELSFREGDALTIMSRRDdseTEWWWAKVNDKEGYVPRN 1061
Cdd:cd11840     2 VIALFPYTAQNEDELSFQKGDIINVLSKDD---PDWWRGELNGQTGLFPSN 49

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

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gi 688593794 1013 ALWDYEAQSADELSFREGDALTIMSRRDDsetEWWWAKVNDKEGYVPRN 1061
Cdd:cd11817     4 ALYDFTGETEEDLSFQRGDRILVTEHLDA---EWSRGRLNGREGIFPRA 49

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases 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). 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.

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gi 688593794 1013 ALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAK--VNDKEGYVPRN 1061
Cdd:cd12007     5 ALYDYEARTTEDLSFKKGERFQII---NNTEGDWWEARsiATGKNGYIPSN 52

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 688593794 1013 ALWDYEAQSADELSFREGDALTIMSRRDDSETEWWWAKVNDKEGYVPRNLLGLYP 1067
Cdd:cd12003     5 ALYDNAAESPEELSFRRGDVLMVLKREHGSLPGWWLCSLHGQQGIAPANRLRLLP 59

Src homology 3 domain of Alpha Spectrin; Spectrin is a major structural component of the red blood cell membrane skeleton and is important in erythropoiesis and membrane biogenesis. It is a flexible, rope-like molecule composed of two subunits, alpha and beta, which consist of many spectrin-type repeats. Alpha and beta spectrin associate to form heterodimers and tetramers; spectrin tetramer formation is critical for red cell shape and deformability. Defects in alpha spectrin have been associated with inherited hemolytic anemias including hereditary spherocytosis (HSp), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP). Alpha spectrin contains a middle SH3 domain and a C-terminal EF-hand binding motif in addition to multiple spectrin repeats. 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 688593794 1011 VYALWDYEAQSADELSFREGDALTIMSrrdDSETEWWWAKVNDKEGYVPRNLL 1063
Cdd:cd11808     2 VVALYDYQEKSPREVSMKKGDILTLLN---SSNKDWWKVEVNDRQGFVPAAYV 51

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 688593794 1013 ALWDYEAQSADELSFREGDALTIMsrrDDSETEWWWAKVNDKEGYVPRNLLGLY 1066
Cdd:cd11975     9 AVWDHVTMANRELAFKAGDVIKVL---DASNKDWWWGQIDDEEGWFPASFVRLW 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 688593794 1013 ALWDYEAQSADELSFREGDALTIMSrrDDSETEWWWAKVNDKEGYVPRNLL 1063
Cdd:cd11946     5 AKYDFKATADDELSFKRGDILKVLN--EECDQNWYKAELNGKDGFIPKNYI 53