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 1034560520  906 AGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 985
Cdd:cd15988      1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  986 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1065
Cdd:cd15988     81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1066 LVNMLIGIIVFNKLMARDGISDKSKKQRAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLALTW 1145
Cdd:cd15988    161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGSEAEPCSSLLLKCSKCGVVSSAAMSSATASSAMASLWSSCVVLPLLALTW 240

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1034560520 1146 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1196
Cdd:cd15988    241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

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 1034560520  614 GMSQVVRSLQELLARRTYYSGDLLFSVDILRNVTDTFKRATYVPSADDVQ-----VS------------------PGSVH 670
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLEnfvqtVSnlldpenreswedlqqteRGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  671 --LLRVVEDFIHLVGDALKAFQSSLIVTDNLVISIQRE--PVSAVSSDITFPMRGRRGmkdwvrHSEDRLFLPKEVLSLS 746
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLdtHNFKGARFPRFPMKGERP------KDEDSVKLPPKAFKPP 154

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 1034560520   847 TDPHCASWDYSRadassGDWDTENCQTLETQAAHTRCQCQHLSTFAVLAQPPKD 900
Cdd:smart00303    1 FNPICVFWDESS-----GEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPPI 49

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1034560520   478 WGPWNAWSLCSKTCDTGWQRRFRMC--QATGTQGYPCEGTGEEVKPCSEKRCP 528
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcsPPPQNGGGPCTGEDVETRACNEQPCP 53

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1034560520   531 HEMCRDEYVMLMTWKKAAAGEIIYNKCPPNASG-----SASRRCLLSAQgvayWGL--PSFARCISHEYRYL 595
Cdd:smart00008    2 DLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGfsyktGASRNCTENGG----WSPpfPNYSNCTSNDYEEL 69

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 1034560520  906 AGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 985
Cdd:cd15988      1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  986 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1065
Cdd:cd15988     81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1066 LVNMLIGIIVFNKLMARDGISDKSKKQRAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLALTW 1145
Cdd:cd15988    161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGSEAEPCSSLLLKCSKCGVVSSAAMSSATASSAMASLWSSCVVLPLLALTW 240

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1034560520 1146 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1196
Cdd:cd15988    241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

7 transmembrane receptor (Secretin family); This family is known as Family B, the secretin-receptor family or family 2 of the G-protein-coupled receptors (GCPRs). They have been described in many animal species, but not in plants, fungi or prokaryotes. Three distinct sub-families are recognized. Subfamily B1 contains classical hormone receptors, such as receptors for secretin and glucagon, that are all involved in cAMP-mediated signalling pathways. Subfamily B2 contains receptors with long extracellular N-termini, such as the leukocyte cell-surface antigen CD97; calcium-independent receptors for latrotoxin, and brain-specific angiogenesis inhibitors amongst others. Subfamily B3 includes Methuselah and other Drosophila proteins. Other than the typical seven-transmembrane region, characteriztic structural features include an amino-terminal extracellular domain involved in ligand binding, and an intracellular loop (IC3) required for specific G-protein coupling.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  906 AGSPSVPLVIGCAVSCMALLTLLAIYAAFwRFIKSERSIILLNFCLSILASNILILVGQSRVLSKG--------VCTMTA 977
Cdd:pfam00002    1 ALSLKVIYTVGYSLSLVALLLAIAIFLLF-RKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKQdldhcswvGCKVVA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  978 AFLHFFFLSSFCWVLTEAWQSYLA-VIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTrTKGYGTSSYCWLSLEGGLLYA 1056
Cdd:pfam00002   80 VFLHYFFLANFFWMLVEGLYLYTLlVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVD-PKGYGEDDGCWLSNENGLWWI 158

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1057 FVGPAAVIVLVNMLIGIIVFNKLMARDGISDKSKKQRagsercpwaslllpcsacgavpspllssasaRNAMASLWSSCV 1136
Cdd:pfam00002  159 IRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDL-------------------------------KQYRRLAKSTLL 207

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 1034560520 1137 VLPLLALTWMSAVLAMTDRR--SVLFQALFAVFNSAQGFVI 1175
Cdd:pfam00002  208 LLPLLGITWVFGLFAFNPENtlRVVFLYLFLILNSFQGFFV 248

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1034560520   367 WEEWGSWSLCSRSCGRGSRSRMRTCV--PPQHGGKACEGPELQTKLCSMAACP 417
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspPPQNGGGPCTGEDVETRACNEQPCP 53

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 1034560520  849 PHCASWDYSraDASSGDWDTENCQTLETQAAHTRCQCQHLSTFAVL 894
Cdd:pfam01825    1 PQCVFWDFT--NSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1034560520  369 EWGSWSLCSRSCGRGSRSRMRT-CVPPQHGGKACeGPELQTKLCSMAAC 416
Cdd:pfam19028    5 EWSEWSECSVTCGGGVQTRTRTvIVEPQNGGRPC-PELLERRPCNLPPC 52

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1034560520   422 WLEWGPWGPCSTSCANGTQQRSRKCSVAGPAW--ATCTGALTDTRECSNLECP 472
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNggGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 1034560520  424 EWGPWGPCSTSCANGTQQRSRKCSVAGPAWATCTGALTDTRECSNLEC 471
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1034560520  479 GPWNAWSLCSKTCDTGWQRRFRMCQATGTQGYPCEGTGEEVKPCSEKRC 527
Cdd:pfam00090    1 SPWSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

sporozoite surface protein 2 (SSP2); Provisional

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1034560520  359 ATCpvhGVWEEWgswSLCSRSCGRGSRSRMRtcvPPQHGGkaCEgPELQTKlCSMAACPVE 419
Cdd:PTZ00441   238 ASC---GPWDEW---TPCSVTCGKGTHSRSR---PILHEG--CT-THMVEE-CEEEECPVE 285

Hormone receptor domain; This extracellular domain contains four conserved cysteines that probably for disulphide bridges. The domain is found in a variety of hormone receptors. It may be a ligand binding domain.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1034560520  531 HEMCRDEYVMLMTWKKAAAGEIIYNKCPPNAS-----GSASRRCLLSAQgvayWGLPS---FARCISH 590
Cdd:pfam02793    1 GLGCPRTWDGILCWPRTPAGETVEVPCPDYFSgfdprGNASRNCTEDGT----WSEHPpsnYSNCTSN 64

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 1034560520  906 AGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 985
Cdd:cd15988      1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  986 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1065
Cdd:cd15988     81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1066 LVNMLIGIIVFNKLMARDGISDKSKKQRAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLALTW 1145
Cdd:cd15988    161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGSEAEPCSSLLLKCSKCGVVSSAAMSSATASSAMASLWSSCVVLPLLALTW 240

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1034560520 1146 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1196
Cdd:cd15988    241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

brain-specific angiogenesis inhibitor 3, 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 1034560520  904 ELAGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFF 983
Cdd:cd15989      1 ESSGTPSVTLIVGCGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKGICTMTTAFLHFF 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  984 FLSSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAV 1063
Cdd:cd15989     81 FLASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVAISMGFTKAKGYGTPHYCWLSLEGGLLYAFVGPAAA 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1064 IVLVNMLIGIIVFNKLMARDGISDKSKKQRAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLAL 1143
Cdd:cd15989    161 VVLVNMVIGILVFNKLVSRDGILDKKLKHRAGQMSEPHSGLTLKCAKCGVVSTTALSATTASNAMASLWSSCVVLPLLAL 240

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1034560520 1144 TWMSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQM 1194
Cdd:cd15989    241 TWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQDAFRCRL 291

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 1034560520   38 SACSALASGVLYGAFSLQDLFPTIASGCSWTLENPDPTKYSLYLRFNRQEQVCAHFAPRLLPLDHYLVNFTclrpspeea 117
Cdd:pfam19188    1 DPCSTLVQGVLYGSFSLRDLFPTNASGCSWTLENPDPTKYTLYLKFTKPTQSCLPFSPRLLQFDHYLENTT--------- 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  118 vaqaESEVGRPEEEEAeaaagLELCSGSGPFTFLHFDKNFVQLCLSAEPSEAPRLLAPAALAFRFVEVLLINNNNSSQFT 197
Cdd:pfam19188   72 ----RTYLGRESFDEV-----VELCDASSPFSFLEFDKNFVQLCLLAEPRGDPESVVPGPSGDFKVEVLVINNENPSQFT 142

                          170       180       190
                   ....*....|....*....|....*....|....*
gi 1034560520  198 CGVLCRWSEECGRAA--GRACGFAQPGCSCPGEAG 230
Cdd:pfam19188  143 CGVLCRWLEECLSAStsSRPCGIMQTPCICPGTVP 177

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 1034560520  915 IGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 994
Cdd:cd15040     10 IGCGLSLLGLLLTIITYILFRKLRKRKPTKILLNLCLALLLANLLFLFGINSTDNPVLCTAVAALLHYFLLASFMWMLVE 89

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  995 AWQSYLAVIGRMRT--RLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIG 1072
Cdd:cd15040     90 ALLLYLRLVKVFGTypRHFILKYALIGWGLPLIIVIITLAVDPDSYGNSSGYCWLSNGNGLYYAFLGPVLLIILVNLVIF 169

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1073 IIVFNKLMARDGISDKSKKQragsercpwaslllpcsacgavpspllssasarNAMASLWSSCVVLPLLALTWMSAVLAM 1152
Cdd:cd15040    170 VLVLRKLLRLSAKRNKKKRK---------------------------------KTKAQLRAAVSLFFLLGLTWIFGILAI 216

                          250       260       270
                   ....*....|....*....|....*....|....*.
gi 1034560520 1153 TDRRSVlFQALFAVFNSAQGFVITAVHCFLRREVQD 1188
Cdd:cd15040    217 FGARVV-FQYLFAIFNSLQGFFIFIFHCLRNKEVRK 251

orphan GPR133 and related proteins, group V adhesion GPCRs, member of class B2 family of seven-transmembrane G protein-coupled receptors; group V adhesion GPCRs include orphan receptors GPR133, GPR144, and closely related proteins. The function of GPR144 has not yet been characterized, whereas GPR133 is highly expressed in the pituitary gland and is coupled to the G(s) protein, leading to activation of adenylate cyclase pathway. Moreover, genetic variations in the GPR133 have been reported to be associated with adult height and heart rate. 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. 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 1034560520  915 IGCAVSCMALLTLLAIYAaFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 994
Cdd:cd15933     10 IGCGISIACLALTLIIFL-VLRVLSSDRFQIHKNLCVALLLAQILLLAGEWAEGNKVACKVVAILLHFFFMAAFSWMLVE 88

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  995 AWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFtRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIGII 1074
Cdd:cd15933     89 GLHLYLMIVKVFNYKSKMRYYYFIGWGLPAIIVAISLAI-LFDDYGSPNVCWLSLDDGLIWAFVGPVIFIITVNTVILIL 167

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1075 VFNKLMARDGISDKSKKQRagsercpWASLllpcsacgavpspllsSASARnAMAslwsscVVLPLLALTWMSAVLAMTD 1154
Cdd:cd15933    168 VVKITVSLSTNDAKKSQGT-------LAQI----------------KSTAK-ASV------VLLPILGLTWLFGVLVVNS 217

                          250       260       270
                   ....*....|....*....|....*....|....
gi 1034560520 1155 rRSVLFQALFAVFNSAQGFVITAVHCFLRREVQD 1188
Cdd:cd15933    218 -QTIVFQYIFVILNSLQGLMIFLFHCVLNSEVRS 250

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 1034560520  915 IGCAVSCMALLtlLAIYA-AFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLT 993
Cdd:cd15252     10 VGIIISLVCLA--ICIFTfWFFRGLQSDRTTIHKNLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFAWMFI 87

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  994 EAWQSYLAVIGRMRTR-LVRKRFLCLGWGLPALVVAVSVGFTrTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNML-I 1071
Cdd:cd15252     88 EGIQLYLMLVEVFENEgSRHKNFYIFGYGSPAVIVGVSAALG-YRYYGTTKVCWLSTENYFIWSFIGPATLIILLNLIfL 166

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1072 GIIVFnklmardgisdkskkqragsERCPWASLLLPCSACGAvpspllssasarNAMASLWSSCVVLPLLALTWMSAVLA 1151
Cdd:cd15252    167 GVAIY--------------------KMFRHTAGLKPEVSCLE------------NIRSWARGAIALLFLLGLTWIFGVLH 214

                          250       260       270
                   ....*....|....*....|....*....|....*.
gi 1034560520 1152 MtDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQ 1187
Cdd:cd15252    215 I-NHASVVMAYLFTVSNSLQGMFIFLFHCVLSRKVR 249

cadherin EGF LAG seven-pass G-type receptors, group IV adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; The group IV adhesion GPCRs include the cadherin EGF LAG seven-pass G-type receptors (CELSRs) and their Drosophila homolog Flamingo (also known as Starry night). These receptors are also classified as that belongs to the EGF-TM7 group of subfamily B2 adhesion GPCRs, because they contain EGF-like domains. Functionally, the group IV receptors act as key regulators of many physiological processes such as endocrine cell differentiation, neuronal migration, dendrite growth, axon, guidance, lymphatic vessel and valve formation, and planar cell polarity (PCP) during embryonic development. The 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. In the case of CELSR/Flamingo/Starry night, their extracellular domains comprise nine cadherin repeats linked to a series of epidermal growth factor (EGF)-like and laminin globular (G)-like domains. The cadherin repeats contain sequence motifs that mediate calcium-dependent cell-cell adhesion by homophilic interactions. 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. Three mammalian orthologs of Flamingo, Celsr1-3, are widely expressed in the nervous system from embryonic development until the adult stage. Each Celsr exhibits different expression patterns in the developing brain, suggesting that they serve distinct functions. Mutations of CELSR1 cause neural tube defects in the nervous system, while mutations of CELSR2 are associated with coronary heart disease. Moreover, CELSR1 and several other PCP signaling molecules, such as dishevelled, prickle, frizzled, have been shown to be upregulated in B lymphocytes of chronic lymphocytic leukemia patients. Celsr3 is expressed in both the developing and adult mouse brain. It has been functionally implicated in proper neuron migration and axon guidance in the CNS.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  915 IGCAVSCMALLTLLAIYAAFwRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 994
Cdd:cd15441     10 IGIGISLVLLVIAFLVLSCL-RGLQSNSNSIHKNLVACLLLAELLFLLGINQTENLFPCKLIAILLHYFYLSAFSWLLVE 88

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  995 AWQSYlavigRMRT--RLVRK---RF-LCLGWGLPALVVAVSVGFtRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVN 1068
Cdd:cd15441     89 SLHLY-----RMLTepRDINHghmRFyYLLGYGIPAIIVGLSVGL-RPDGYGNPDFCWLSVNETLIWSFAGPIAFVIVIT 162

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1069 MLIGIivfnkLMARDGISDKSKKQRAGSERcpwaslllpcsacgavpspllssasarnamASLWSSCVVLPLLALTWMSA 1148
Cdd:cd15441    163 LIIFI-----LALRASCTLKRHVLEKASVR------------------------------TDLRSSFLLLPLLGATWVFG 207

                          250       260       270
                   ....*....|....*....|....*....|....*...
gi 1034560520 1149 VLAMTDrRSVLFQALFAVFNSAQGFVITAVHCFLRREV 1186
Cdd:cd15441    208 LLAVNE-DSELLHYLFAGLNFLQGLFIFLFYCIFNKKV 244

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 1034560520  915 IGCAVSCMALLTLLAIYAAFWRFIKSE-----RSIILLNFCLSILASNILILVG---QSRVLSKGVCTMTAAFLHFFFLS 986
Cdd:cd15932     10 VGLGISILSLVLCLIIEALVWKSVTKNktsymRHVCLVNIALSLLIADIWFIIGaaiSTPPNPSPACTAATFFIHFFYLA 89

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520  987 SFCWVLTeawqsyLAVIGRMRTRLV-----RKRFL----CLGWGLPALVVAVSVGFTR-TKGYGTSSYCWLSL-EGGLLY 1055
Cdd:cd15932     90 LFFWMLT------LGLLLFYRLVLVfhdmsKSTMMaiafSLGYGCPLIIAIITVAATApQGGYTRKGVCWLNWdKTKALL 163

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034560520 1056 AFVGPAAVIVLVNMLIGIIVFNKLMaRDGISDKSKKQRagsercpwaslllpcsacgavpspllssasaRNAMASLWSSC 1135
Cdd:cd15932    164 AFVIPALAIVVVNFIILIVVIFKLL-RPSVGERPSKDE-------------------------------KNALVQIGKSV 211

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1034560520 1136 VVL-PLLALTWMSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVK 1191
Cdd:cd15932    212 AILtPLLGLTWGFGLGTMIDPKSLAFHIIFAILNSFQGFFILVFGTLLDSKVREALL 268

Epidermal Growth Factor, latrophilin and seven transmembrane domain-containing protein 1; member of the class B2 family of seven-transmembrane G protein-coupled receptors; ETL (EGF-TM7-latrophilin-related protein) belongs to Group I adhesion GPCRs, which also include latrophilins (also called lectomedins or latrotoxin receptors). 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. ETL, for instance, contains EGF-like repeats, which also present in other EGF-TM7 adhesion GPCRs, such as Cadherin EGF LAG seven-pass G-type receptors (CELSR1-3), EGF-like module receptors (EMR1-3), CD97, and Flamingo. ETL is highly expressed in heart, where developmentally regulated, as well as in normal smooth cells. 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.