brain-specific angiogenesis inhibitors, group VII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all adhesion receptors, are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediate direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  874 SGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFL 953
Cdd:cd15251      1 AGSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  954 ASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVV 1033
Cdd:cd15251     81 SSFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1034 LVNMVIGILVFNKLVSRDGILDkklkhRAGASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMV 1113
Cdd:cd15251    161 LVNMVIGILVFNKLVSRDGISD-----NAMASLWSSCVVLPLLALTWMSAVLAMTDRRSVLFQILFAVFDSLQGFVIVMV 235

                          250
                   ....*....|....*...
gi 1907068045 1114 HCILRREVQDAFRCRLRN 1131
Cdd:cd15251    236 HCILRREVQDAVKCRMGV 253

GPCR-Autoproteolysis INducing (GAIN) domain; The GAIN a domain of alpha-helices and beta-strands that is found in cell-adhesion GPCRs and precedes the GPS motif where the autoproteolysis occurs, family, pfam01825. The full GAIN domain, comprises the GPS and the GAIN, in cell-adhesion GPCRs, and is the functional unit for autoproteolysis. The GPS motif at the end of the GAIN domain is an ancient domain that exists in primitive ancestor organizms, and the full GAIN + GPS is conserved in all cell-adhesion GPCRs and all PKD1-related proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  594 GMSQVTKTLLDLTQRKNFYAGDLLVSVEILRNVTDTFKRASYIPASDGVQNFFQIVSNLLDEENKEKWEDAQQIYPGSIE 673
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  674 --LMQVIEDFIHIVGMGMMDFQNSYLMTGNVVASIQKL--PAASVLTDINFPMKGRKGmvdwarNSEDRVVIPKSIFtpv 749
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLdtHNFKGARFPRFPMKGERP------KDEDSVKLPPKAF--- 151

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907068045  750 ssKELDESSVFVLGAVLYKNLDLILPTLRNY-----------TVVNSKVIVVTIRP 794
Cdd:pfam16489  152 --KPPDSNGTVVVVFILYRNLGSLLPPSSRYdpdrrslrlprRVVNSPVVSASVHS 205

G-protein-coupled receptor proteolytic site domain; Present in latrophilin/CL-1, sea urchin REJ and polycystin.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1907068045   816 NPYCVLWDdsksnESLGTWSTQGCKTVLTDASHTKCLCDRLSTFAILAQQPR 867
Cdd:smart00303    2 NPICVFWD-----ESSGEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPP 48

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1907068045   296 EWSQWSACSVTCGQGSQVRTRTCVSPY----GTHCSGPLRESRVCnNTALCP 343
Cdd:smart00209    3 EWSEWSPCSVTCGGGVQTRTRSCCSPPpqngGGPCTGEDVETRAC-NEQPCP 53

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907068045   510 PYEICPEDYLISMVWKRTPAGDLAFNQCPLNATG-----TTSRRCSLSLhgvaSWEQ--PSFARCISNEYRHLQ 576
Cdd:smart00008    1 TDLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGfsyktGASRNCTENG----GWSPpfPNYSNCTSNDYEELK 70

brain-specific angiogenesis inhibitors, group VII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all adhesion receptors, are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediate direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  874 SGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFL 953
Cdd:cd15251      1 AGSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  954 ASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVV 1033
Cdd:cd15251     81 SSFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1034 LVNMVIGILVFNKLVSRDGILDkklkhRAGASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMV 1113
Cdd:cd15251    161 LVNMVIGILVFNKLVSRDGISD-----NAMASLWSSCVVLPLLALTWMSAVLAMTDRRSVLFQILFAVFDSLQGFVIVMV 235

                          250
                   ....*....|....*...
gi 1907068045 1114 HCILRREVQDAFRCRLRN 1131
Cdd:cd15251    236 HCILRREVQDAVKCRMGV 253

Adhesion GPCR B N-terminal region; This region is found at the N-terminus of various adhesion G-protein coupled receptor B proteins. This region contains 10 cysteine residues that probably form disulphide bonds.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045   30 CSTLVKGVIYGSYSVSEMFPKNFTNCTWTLENPDPTKYSIYLKFSKKDLSCSNFSLLAYQFDHFSHEKIKDLLRKNH--S 107
Cdd:pfam19188    3 CSTLVQGVLYGSFSLRDLFPTNASGCSWTLENPDPTKYTLYLKFTKPTQSCLPFSPRLLQFDHYLENTTRTYLGRESfdE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  108 IMQLCSSKNAFVFLQYDKNFIQIRRVFPTDFPGLQKKVEEDQKSFFEFLVLNKVSPSQFGCHVLCTWLESCLKSENGrTE 187
Cdd:pfam19188   83 VVELCDASSPFSFLEFDKNFVQLCLLAEPRGDPESVVPGPSGDFKVEVLVINNENPSQFTCGVLCRWLEECLSASTS-SR 161

                          170
                   ....*....|....
gi 1907068045  188 SCGIMYTKCTCPQH 201
Cdd:pfam19188  162 PCGIMQTPCICPGT 175

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1907068045   348 WEEWSPWSLCSFTCGRGQRTRTRSCT--PPQYGGRPCEGPETHHKPCNIALCP 398
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspPPQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1907068045   403 WQEWSSWSHCSVTCSNGTQQRSRQCT--AAAHGGSECRGPWAESRECYNPEC 452
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspPPQNGGGPCTGEDVETRACNEQPC 52

GPCR proteolysis site, GPS, motif; The GPS motif is found in GPCRs, and is the site for auto-proteolysis, so is thus named, GPS. The GPS motif is a conserved sequence of ~40 amino acids containing canonical cysteine and tryptophan residues, and is the most highly conserved part of the domain. In most, if not all, cell-adhesion GPCRs these undergo autoproteolysis in the GPS between a conserved aliphatic residue (usually a leucine) and a threonine, serine, or cysteine residue. In higher eukaryotes this motif is found embedded in the C-terminal beta-stranded part of a GAIN domain - GPCR-Autoproteolysis INducing (GAIN). The GAIN-GPS domain adopts a fold in which the GPS motif, at the C-terminus, forms five beta-strands that are tightly integrated into the overall GAIN domain. The GPS motif, evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. The GAIN-GPS domain is both necessary and sufficient functionally for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyze peptide bond hydrolysis. In the cell-adhesion GPCRs and PKD proteins, the GPS motif is always located at the end of their long N-terminal extracellular regions, immediately before the first transmembrane helix of the respective protein.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1907068045  817 PYCVLWDDSksNESLGTWSTQGCKTVLTDASHTKCLCDRLSTFAIL 862
Cdd:pfam01825    1 PQCVFWDFT--NSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1907068045  296 EWSQWSACSVTCGQGSQVRTRTCVS--PYGTHCSGPLRESRVCN 337
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTCKSpfPGGEPCTGDDIETQACK 45

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1907068045  404 QEWSSWSHCSVTCSNGTQQRSRQCTAAAHGGSECRGPWAESRECYNPEC 452
Cdd:pfam00090    1 SPWSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1907068045  461 WGHWSGCSKSCDGGWERRMRTCQGAAVTGQQCEGTGEEVRRCSEQRC 507
Cdd:pfam00090    3 WSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

thrombosponding-related protein; Provisional

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1907068045  296 EWSQWSACSVTCGQ--GSQVRTRTCVSPYGTHCSGPLRESRVC 336
Cdd:PTZ00087   235 EWGEWSNCSMECDHpdNVQIRERKCAHPSGDCFKGDLKETRPC 277

thrombosponding-related protein; Provisional

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1907068045  403 WQEWSSWSHCSVTCS--NGTQQRSRQCtaaAHGGSEC-RGPWAESRECYNP 450
Cdd:PTZ00087   233 YTEWGEWSNCSMECDhpDNVQIRERKC---AHPSGDCfKGDLKETRPCQVP 280

brain-specific angiogenesis inhibitors, group VII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all adhesion receptors, are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediate direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  874 SGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFL 953
Cdd:cd15251      1 AGSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  954 ASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVV 1033
Cdd:cd15251     81 SSFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1034 LVNMVIGILVFNKLVSRDGILDkklkhRAGASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMV 1113
Cdd:cd15251    161 LVNMVIGILVFNKLVSRDGISD-----NAMASLWSSCVVLPLLALTWMSAVLAMTDRRSVLFQILFAVFDSLQGFVIVMV 235

                          250
                   ....*....|....*...
gi 1907068045 1114 HCILRREVQDAFRCRLRN 1131
Cdd:cd15251    236 HCILRREVQDAVKCRMGV 253

brain-specific angiogenesis inhibitor 2, a group VII adhesion GPCR, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all adhesion receptors, are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediates direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  874 SGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFL 953
Cdd:cd15988      1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  954 ASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVV 1033
Cdd:cd15988     81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1034 LVNMVIGILVFNKLVSRDGILDKKLKHRAG---------------------------------ASLWSSCVVLPLLALTW 1080
Cdd:cd15988    161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGseaepcsslllkcskcgvvssaamssatassamASLWSSCVVLPLLALTW 240

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|....*....
gi 1907068045 1081 MSAVLAMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQDAFRCRL 1129
Cdd:cd15988    241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQM 289

adhesion receptors, subfamily B2 of the class B family of seven-transmembrane G protein-coupled receptors; The B2 subfamily of class B GPCRs consists of cell-adhesion receptors with 33 members in humans and vertebrates. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing a variety of structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, linked to a class B seven-transmembrane domain. These include, for example, EGF (epidermal growth factor)-like domains in CD97, Celsr1 (cadherin family member), Celsr2, Celsr3, EMR1 (EGF-module-containing mucin-like hormone receptor-like 1), EMR2, EMR3, and Flamingo; two laminin A G-type repeats and nine cadherin domains in Flamingo and its human orthologs Celsr1, Celsr2 and Celsr3; olfactomedin-like domains in the latrotoxin receptors; and five or four thrombospondin type 1 repeats in BAI1 (brain-specific angiogenesis inhibitor 1), BAI2 and BAI3. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  878 SVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFLASFC 957
Cdd:cd15040      5 SIITYIGCGLSLLGLLLTIITYILFRKLRKRKPTKILLNLCLALLLANLLFLFGINSTDNPVLCTAVAALLHYFLLASFM 84

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  958 WVLTEAWQSYMAVTG--KIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVVLV 1035
Cdd:cd15040     85 WMLVEALLLYLRLVKvfGTYPRHFILKYALIGWGLPLIIVIITLAVDPDSYGNSSGYCWLSNGNGLYYAFLGPVLLIILV 164

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1036 NMVIGILVFNKLVSRDGILDKKLKHRAGASLWSSCVVLPLLALTWMSAVLAMTDKRSIlFQILFAVFDSLQGFVIVMVHC 1115
Cdd:cd15040    165 NLVIFVLVLRKLLRLSAKRNKKKRKKTKAQLRAAVSLFFLLGLTWIFGILAIFGARVV-FQYLFAIFNSLQGFFIFIFHC 243

                          250
                   ....*....|
gi 1907068045 1116 ILRREVQDAF 1125
Cdd:cd15040    244 LRNKEVRKAW 253

Adhesion GPCR B N-terminal region; This region is found at the N-terminus of various adhesion G-protein coupled receptor B proteins. This region contains 10 cysteine residues that probably form disulphide bonds.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045   30 CSTLVKGVIYGSYSVSEMFPKNFTNCTWTLENPDPTKYSIYLKFSKKDLSCSNFSLLAYQFDHFSHEKIKDLLRKNH--S 107
Cdd:pfam19188    3 CSTLVQGVLYGSFSLRDLFPTNASGCSWTLENPDPTKYTLYLKFTKPTQSCLPFSPRLLQFDHYLENTTRTYLGRESfdE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  108 IMQLCSSKNAFVFLQYDKNFIQIRRVFPTDFPGLQKKVEEDQKSFFEFLVLNKVSPSQFGCHVLCTWLESCLKSENGrTE 187
Cdd:pfam19188   83 VVELCDASSPFSFLEFDKNFVQLCLLAEPRGDPESVVPGPSGDFKVEVLVINNENPSQFTCGVLCRWLEECLSASTS-SR 161

                          170
                   ....*....|....
gi 1907068045  188 SCGIMYTKCTCPQH 201
Cdd:pfam19188  162 PCGIMQTPCICPGT 175

class B family of seven-transmembrane G protein-coupled receptors; The class B of seven-transmembrane GPCRs is classified into three major subfamilies: subfamily B1 (secretin-like receptor family), B2 (adhesion family), and B3 (Methuselah-like family). The class B receptors have been identified in all the vertebrates, from fishes to mammals, as well as invertebrates including Caenorhabditis elegans and Drosophila melanogaster, but are not present in plants, fungi or prokaryotes. The B1 subfamily comprises receptors for polypeptide hormones of 27-141 amino-acid residues such as secretin, glucagon, glucagon-like peptide (GLP), calcitonin gene-related peptide, parathyroid hormone (PTH), and corticotropin-releasing factor. These receptors contain the large N-terminal extracellular domain (ECD), which plays a critical role in hormone recognition by binding to the C-terminal portion of the peptide. On the other hand, the N-terminal segment of the hormone induces receptor activation by interacting with the receptor transmembrane domains and connecting extracellular loops, triggering intracellular signaling pathways. All members of the subfamily B1 receptors preferentially couple to G proteins of G(s) family, which positively stimulate adenylate cyclase, leading to increased intracellular cAMP formation and calcium influx. The subfamily B2 consists of cell-adhesion receptors with 33 members in humans and vertebrates. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing a variety of structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, linked to a class B seven-transmembrane domain. These include, for example, EGF (epidermal growth factor)-like domains in CD97, Celsr1 (cadherin family member), Celsr2, Celsr3, EMR1 (EGF-module-containing mucin-like hormone receptor-like 1), EMR2, EMR3, and Flamingo; two laminin A G-type repeats and nine cadherin domains in Flamingo and its human orthologs Celsr1, Celsr2 and Celsr3; olfactomedin-like domains in the latrotoxin receptors; and five or four thrombospondin type 1 repeats in BAI1 (brain-specific angiogenesis inhibitor 1), BAI2 and BAI3. Almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. Furthermore, the subfamily B3 includes Methuselah (Mth) protein, which was originally identified in Drosophila as a GPCR affecting stress resistance and aging, and its closely related proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  882 IVGSGLSCLALITLAVVYAALWRYiRSERSIILINFCLSIISSNILILVGQTQTHNKS--ICTTTTAFLHFFFLASFCWV 959
Cdd:cd13952      9 YIGCSLSLVGLLLTIITYLLFPKL-RNLRGKILINLCLSLLLAQLLFLIGQLLTSSDRpvLCKALAILLHYFLLASFFWM 87

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  960 LTEAWQSYMAVTGKIRTRlIRKRFL---CLGWGLPALVVATSVGFTRT----KGYGTDHYCWLSLEGGLLYAFVGPAAAV 1032
Cdd:cd13952     88 LVEAFDLYRTFVKVFGSS-ERRRFLkysLYGWGLPLLIVIITAIVDFSlygpSPGYGGEYCWLSNGNALLWAFYGPVLLI 166

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1033 VLVNMVIGILVFNKLVSRDGILDKKLKHRA-GASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQGFVIV 1111
Cdd:cd13952    167 LLVNLVFFILTVRILLRKLRETPKQSERKSdRKQLRAYLKLFPLMGLTWIFGILAPFVGGSLVFWYLFDILNSLQGFFIF 246

                          250
                   ....*....|....
gi 1907068045 1112 MVHCILRREVQDAF 1125
Cdd:cd13952    247 LIFCLKNKEVRRLL 260

GPCR-Autoproteolysis INducing (GAIN) domain; The GAIN a domain of alpha-helices and beta-strands that is found in cell-adhesion GPCRs and precedes the GPS motif where the autoproteolysis occurs, family, pfam01825. The full GAIN domain, comprises the GPS and the GAIN, in cell-adhesion GPCRs, and is the functional unit for autoproteolysis. The GPS motif at the end of the GAIN domain is an ancient domain that exists in primitive ancestor organizms, and the full GAIN + GPS is conserved in all cell-adhesion GPCRs and all PKD1-related proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  594 GMSQVTKTLLDLTQRKNFYAGDLLVSVEILRNVTDTFKRASYIPASDGVQNFFQIVSNLLDEENKEKWEDAQQIYPGSIE 673
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  674 --LMQVIEDFIHIVGMGMMDFQNSYLMTGNVVASIQKL--PAASVLTDINFPMKGRKGmvdwarNSEDRVVIPKSIFtpv 749
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLdtHNFKGARFPRFPMKGERP------KDEDSVKLPPKAF--- 151

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907068045  750 ssKELDESSVFVLGAVLYKNLDLILPTLRNY-----------TVVNSKVIVVTIRP 794
Cdd:pfam16489  152 --KPPDSNGTVVVVFILYRNLGSLLPPSSRYdpdrrslrlprRVVNSPVVSASVHS 205

CD97 antigen, member of the class B2 family of seven-transmembrane G protein-coupled receptors; group II adhesion GPCRs, including the leukocyte cell-surface antigen CD97 and the epidermal growth factor (EGF)-module-containing, mucin-like hormone receptor (EMR1-4), are primarily expressed in cells of the immune system. All EGF-TM7 receptors, which belong to the B2 subfamily B2 of adhesion GPCRs, are members of group II, except for ETL (EGF-TM7-latrophilin related protein), which is classified into group I. Members of the EGF-TM7 receptors are characterized by the presence of varying numbers of N-terminal EGF-like domains, which play critical roles in ligand recognition and cell adhesion, linked by a stalk region to a class B seven-transmembrane domain. In the case of CD97, alternative splicing results in three isoforms possessing either three (EGF1,2,5), four (EGF1,2,3,5) or five (EGF1,2,3,4,5) EGF-like domains. Moreover, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. For example, CD97, which is involved in angiogenesis and the migration and invasion of tumor cells, has been shown to promote cell aggregation in a GPS proteolysis-dependent manner. CD97 is widely expressed on lymphocytes, monocytes, macrophages, dendritic cells, granulocytes and smooth muscle cells as well as in a variety of human tumors including colorectal, gastric, esophageal pancreatic, and thyroid carcinoma. EMR2 shares strong sequence homology with CD97, differing by only six amino acids. However, unlike CD97, EMR2 is not found in those of CD97-positive tumor cells and is not expressed on lymphocytes but instead on monocytes, macrophages and granulocytes. CD97 has three known ligands: CD55, decay-accelerating factor for regulation of complement system; chondroitin sulfate, a glycosaminoglycan found in the extracellular matrix; and the integrin alpha5beta1, which play a role in angiogenesis. Although EMR2 does not effectively interact with CD55, the fourth EGF-like domain of this receptor binds to chondroitin sulfate to mediate cell attachment.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  879 VTLIVGSGLS-CLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFLASFC 957
Cdd:cd15438      4 LTLITKVGLSvSLFCLFLCILTFLFCRSIRGTRNTIHLHLCLSLFLAHLIFLLGINNTNNQVACAVVAGLLHYFFLAAFC 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  958 WVLTEAWQSYMAVTGKIRTRLIRKRFLCL-GWGLPALVVATSVGFTrTKGYGTDHYCWLSLEGGLLYAFVGPAAAVVLVN 1036
Cdd:cd15438     84 WMSLEGVELYLMVVQVFNTQSLKKRYLLLiGYGVPLVIVAISAAVN-SKGYGTQRHCWLSLERGFLWSFLGPVCLIILVN 162

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1037 MVIGILVFNKLVSRDGILD---KKLKhRAGASLWSSCVVLPLLALTWMSAVLAMTDkRSILFQILFAVFDSLQGFVIVMV 1113
Cdd:cd15438    163 AIIFVITVWKLAEKFSSINpdmEKLR-KIRALTITAIAQLCILGCTWIFGFFQFSD-STLVMSYLFTILNSLQGLFIFLL 240

                          250
                   ....*....|...
gi 1907068045 1114 HCILRREVQDAFR 1126
Cdd:cd15438    241 HCLLSKQVREEYS 253

Latrophilins and similar receptors, group I adhesion GPCRs, member of class B2 family of seven-transmembrane G protein-coupled receptors; Group I adhesion GPCRs consist of latrophilins (also called lectomedins or latrotoxin receptors) and ETL (EGF-TM7-latrophilin-related protein. These receptors are a member of the adhesion family (subclass B2) that belongs to the class B GPCRs. Three subtypes of latrophilins have been identified: LPH1 (latrophilin-1), LPH2, and LPH3. The latrophilin-1 is a brain-specific calcium-independent receptor of alpha-latrotoxin, a potent presynaptic neurotoxin from the venom of the black widow spider that induces massive neurotransmitter release from sensory and motor neurons as well as endocrine cells, leading to nerve-terminal degeneration. Latrophilin-2 and -3, although sharing strong sequence homology to latrophilin-1, do not bind alpha-latrotoxin. While latrophilin-3 is also brain specific, latrophilin-2 is ubiquitously distributed. The endogenous ligands for these two receptors are unknown. ETL, a seven transmembrane receptor containing EGF-like repeats is highly expressed in heart, where developmentally regulated, as well as in normal smooth cells. The function of the ETL is unknown. All adhesion GPCRs possess large N-terminal extracellular domains containing multiple structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, coupled to a seven-transmembrane domain. In addition, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  883 VGSGLSCLALItLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFLASFCWVLTE 962
Cdd:cd15252     10 VGIIISLVCLA-ICIFTFWFFRGLQSDRTTIHKNLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFAWMFIE 88

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  963 AWQSYMAVTGKIRTR-LIRKRFLCLGWGLPALVVATSVGFTrTKGYGTDHYCWLSLEGGLLYAFVGPAAAVVLVNMV-IG 1040
Cdd:cd15252     89 GIQLYLMLVEVFENEgSRHKNFYIFGYGSPAVIVGVSAALG-YRYYGTTKVCWLSTENYFIWSFIGPATLIILLNLIfLG 167

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1041 ILVFnklvsrdgildKKLKHRAGASLWSSC------------VVLPLLALTWMSAVLAMtDKRSILFQILFAVFDSLQGF 1108
Cdd:cd15252    168 VAIY-----------KMFRHTAGLKPEVSClenirswargaiALLFLLGLTWIFGVLHI-NHASVVMAYLFTVSNSLQGM 235

                          250       260
                   ....*....|....*....|..
gi 1907068045 1109 VIVMVHCILRREVQDAFRCRLR 1130
Cdd:cd15252    236 FIFLFHCVLSRKVRKEYYKLFR 257

orphan GPR116 and related proteins, group IV adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; group VI adhesion GPCRs consist of orphan receptors GPR110, GPR111, GPR113, GPR115, GPR116, and closely related proteins. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in ligand recognition as well as cell-cell adhesion and cell-matrix interactions, linked by a stalk region to a class B seven-transmembrane domain. GPR110 possesses a SEA box in the N-terminal has been identified as an oncogene over-expressed in lung and prostate cancer. GPR113 contains a hormone binding domain and one EGF (epidermal grown factor) domain. GPR112 has extremely long N-terminus (about 2,400 amino acids) containing a number of Ser/Thr-rich glycosylation sites and a pentraxin (PTX) domain. GPR116 has two C2-set immunoglobulin-like repeats, which is found in the members of the immunoglobulin superfamily of cell surface proteins, and a SEA (sea urchin sperm protein, enterokinase, and a grin)-box, which is present in the extracellular domain of the transmembrane mucin (MUC) family and known to enhance O-glycosylation. In addition, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. However, several adhesion GPCRs, including GPR 111, GPR115, and CELSR1, are predicted to be non-cleavable at the GAIN domain because of the lack of a consensus catalytic triad sequence (His-Leu-Ser/Thr) within their GPS.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  877 PSVTLI--VGSGLSCLALITLAVVYAALWRYI-RSE----RSIILINFCLSIISSNILILVG---QTQTHNKSICTTTTA 946
Cdd:cd15932      2 PALDYItyVGLGISILSLVLCLIIEALVWKSVtKNKtsymRHVCLVNIALSLLIADIWFIIGaaiSTPPNPSPACTAATF 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045  947 FLHFFFLASFCWVLTEA----WQSYMAVTGKIRTRLIRKRFlCLGWGLPALVVATSVGFTR-TKGYGTDHYCWLSL-EGG 1020
Cdd:cd15932     82 FIHFFYLALFFWMLTLGlllfYRLVLVFHDMSKSTMMAIAF-SLGYGCPLIIAIITVAATApQGGYTRKGVCWLNWdKTK 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068045 1021 LLYAFVGPAAAVVLVNMVIGILVFNKLVsRDGILD------KKLKHRAGASLwssCVVLPLLALTWMSAVLAMTDKRSIL 1094
Cdd:cd15932    161 ALLAFVIPALAIVVVNFIILIVVIFKLL-RPSVGErpskdeKNALVQIGKSV---AILTPLLGLTWGFGLGTMIDPKSLA 236

                          250       260       270
                   ....*....|....*....|....*....|..
gi 1907068045 1095 FQILFAVFDSLQGFVIVMVHCILRREVQDAFR 1126
Cdd:cd15932    237 FHIIFAILNSFQGFFILVFGTLLDSKVREALL 268