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 568991005  942 TVPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLS 1021
Cdd:cd15251     2 GSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFLS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1022 SFCWVLTEAWQSYMAVTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVL 1101
Cdd:cd15251    82 SFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVVL 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1102 VNMVIGILVFNKLVSKDGITDkklkeragqlpvpplgraltcaecgvlsaaeansdatsNAMASLWSSCVVLPLLALTWM 1181
Cdd:cd15251   162 VNMVIGILVFNKLVSRDGISD--------------------------------------NAMASLWSSCVVLPLLALTWM 203

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 568991005 1182 SAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVD 1231
Cdd:cd15251   204 SAVLAMTDRRSVLFQILFAVFDSLQGFVIVMVHCILRREVQDAVKCRMGV 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 568991005   658 GVSEVIQTLLEISQDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQIISNLLAEENRDKWEEAQLMGPNAKE 737
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005   738 --LFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPAS---GATDISFPMKGWRATGdwakvpEDRVTVSKSVFStg 812
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLDTHnfkGARFPRFPMKGERPKD------EDSVKLPPKAFK-- 152

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 568991005   813 laEADDSSVFVVGTVLYRNLGSFLALQRN-----------TTVLNSKVISVTVKP 856
Cdd:pfam16489  153 --PPDSNGTVVVVFILYRNLGSLLPPSSRydpdrrslrlpRRVVNSPVVSASVHS 205

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 568991005    467 WNEWSSWSTCSASCSQGRQQRTRECNGP--SYGGAECQGHWVETRDCFLQQCP 517
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPppQNGGGPCTGEDVETRACNEQPCP 53

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 568991005    877 TNQTCILWDETDGPsssappqlgpWSWRGCRTVPLDALRTRCLCDRLSTFAILAQLSAD 935
Cdd:smart00303    1 FNPICVFWDESSGE----------WSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPPI 49

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568991005    574 PHEICDEDNFGAVVWKETPAGEVAAVRCPRNATGL-----ILRRCELDEegiaFWEP--PTYIRCVSIDYRNIQ 640
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 568991005  942 TVPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLS 1021
Cdd:cd15251     2 GSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFLS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1022 SFCWVLTEAWQSYMAVTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVL 1101
Cdd:cd15251    82 SFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVVL 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1102 VNMVIGILVFNKLVSKDGITDkklkeragqlpvpplgraltcaecgvlsaaeansdatsNAMASLWSSCVVLPLLALTWM 1181
Cdd:cd15251   162 VNMVIGILVFNKLVSRDGISD--------------------------------------NAMASLWSSCVVLPLLALTWM 203

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 568991005 1182 SAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVD 1231
Cdd:cd15251   204 SAVLAMTDRRSVLFQILFAVFDSLQGFVIVMVHCILRREVQDAVKCRMGV 253

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 568991005   943 VPSVTLIVGCGVSSLTLLMLVIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNK--------VVCTLVAAF 1014
Cdd:pfam00002    3 SLKVIYTVGYSLSLVALLLAIAIFLLF-RKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKqdldhcswVGCKVVAVF 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005  1015 LHFFFLSSFCWVLTEAWQSYMA-VTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTkAKGYSTMNYCWLSLEGGLLYAFV 1093
Cdd:pfam00002   82 LHYFFLANFFWMLVEGLYLYTLlVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVD-PKGYGEDDGCWLSNENGLWWIIR 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005  1094 GPAAAVVLVNMVIGILVFNKLVSKDGITDKKLKERAgqlpvpplgraltcaecgvlsaaeansdatsNAMASLWSSCVVL 1173
Cdd:pfam00002  161 GPILLIILVNFIIFINIVRILVQKLRETNMGKSDLK-------------------------------QYRRLAKSTLLLL 209

                          250       260       270
                   ....*....|....*....|....*....|....*....
gi 568991005  1174 PLLALTWMSAVLAVTDRR--SALFQILFAVFDSLEGFVI 1210
Cdd:pfam00002  210 PLLGITWVFGLFAFNPENtlRVVFLYLFLILNSFQGFFV 248

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 568991005    412 WDEWSPWSLCSSTCGRGFRDRTRTC--RPPQFGGNPCEGPEKQTKFCNIALCP 462
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 568991005    522 WQAWASWGSCSVTCGGGSQRRERVCSGP--FFGGAACQGPQDEYRQCGAQRCP 572
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 568991005    359 EWSPWSVCSSTCGEGWQTRTRFCVSSSYS---TQCSGPLREQRLCNNSAvCP 407
Cdd:smart00209    3 EWSEWSPCSVTCGGGVQTRTRSCCSPPPQnggGPCTGEDVETRACNEQP-CP 53

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 568991005   525 WASWGSCSVTCGGGSQRRERVCSGPFFGGAACQGPQDEYRQCGAQRC 571
Cdd:pfam00090    3 WSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

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        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 568991005   880 TCILWDETDGpsssappQLGPWSWRGCRTVPLDALRTRCLCDRLSTFAIL 929
Cdd:pfam01825    2 QCVFWDFTNS-------TTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 568991005   359 EWSPWSVCSSTCGEGWQTRTRFCVS-SSYSTQCSGPLREQRLCN 401
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTCKSpFPGGEPCTGDDIETQACK 45

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 568991005    264 WKLWSLWGECTRDCGGGLQTRTRTC-LPTLGVEGGGCEGVLEEGRLCNRKAC 314
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcSPPPQNGGGPCTGEDVETRACNEQPC 52

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 568991005  942 TVPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLS 1021
Cdd:cd15251     2 GSPSVTLIVGCGVSCLALLTLLAIYAAFWRYIRSERSIILINFCLSIISSNILILVGQTQTLNKGVCTMTAAFLHFFFLS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1022 SFCWVLTEAWQSYMAVTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVL 1101
Cdd:cd15251    82 SFCWVLTEAWQSYMAVTGRMRTRLIRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAAVVL 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1102 VNMVIGILVFNKLVSKDGITDkklkeragqlpvpplgraltcaecgvlsaaeansdatsNAMASLWSSCVVLPLLALTWM 1181
Cdd:cd15251   162 VNMVIGILVFNKLVSRDGISD--------------------------------------NAMASLWSSCVVLPLLALTWM 203

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 568991005 1182 SAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVD 1231
Cdd:cd15251   204 SAVLAMTDRRSVLFQILFAVFDSLQGFVIVMVHCILRREVQDAVKCRMGV 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 568991005  944 PSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSF 1023
Cdd:cd15988     4 PSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFLSSF 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1024 CWVLTEAWQSYMAVTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVN 1103
Cdd:cd15988    84 CWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIVLVN 163

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1104 MVIGILVFNKLVSKDGITDKKLKERAGQLPVPPLGRALTCAECGVLSAAEANSDATSNAMASLWSSCVVLPLLALTWMSA 1183
Cdd:cd15988   164 MLIGIIVFNKLMSRDGISDKSKKQRAGSEAEPCSSLLLKCSKCGVVSSAAMSSATASSAMASLWSSCVVLPLLALTWMSA 243

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....*.
gi 568991005 1184 VLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRV 1229
Cdd:cd15988   244 VLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQM 289

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 568991005    43 CTTLVQGKFFGYFSAAAVFPANASRCSWTLRNPDPRRYTLYMKVAKAPAPCSgPGRVRTYQFDSFLES-TRTYLGVESFD 121
Cdd:pfam19188    3 CSTLVQGVLYGSFSLRDLFPTNASGCSWTLENPDPTKYTLYLKFTKPTQSCL-PFSPRLLQFDHYLENtTRTYLGRESFD 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005   122 EVLRLCDSSAPLAFLQASKQFLQMQRQQPPQDgdLGPQGEfPSSSDDFSVEYLVVGNRNPSHAACQMLCRWLDACLAGSR 201
Cdd:pfam19188   82 EVVELCDASSPFSFLEFDKNFVQLCLLAEPRG--DPESVV-PGPSGDFKVEVLVINNENPSQFTCGVLCRWLEECLSAST 158

                          170
                   ....*....|....*..
gi 568991005   202 SSHPCGIMQTPCACLGG 218
Cdd:pfam19188  159 SSRPCGIMQTPCICPGT 175

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 568991005   943 VPSVTLIVGCGVSSLTLLMLVIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNK--------VVCTLVAAF 1014
Cdd:pfam00002    3 SLKVIYTVGYSLSLVALLLAIAIFLLF-RKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKqdldhcswVGCKVVAVF 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005  1015 LHFFFLSSFCWVLTEAWQSYMA-VTGRLRSRLVRKRFLCLGWGLPALVVAISVGFTkAKGYSTMNYCWLSLEGGLLYAFV 1093
Cdd:pfam00002   82 LHYFFLANFFWMLVEGLYLYTLlVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVD-PKGYGEDDGCWLSNENGLWWIIR 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005  1094 GPAAAVVLVNMVIGILVFNKLVSKDGITDKKLKERAgqlpvpplgraltcaecgvlsaaeansdatsNAMASLWSSCVVL 1173
Cdd:pfam00002  161 GPILLIILVNFIIFINIVRILVQKLRETNMGKSDLK-------------------------------QYRRLAKSTLLLL 209

                          250       260       270
                   ....*....|....*....|....*....|....*....
gi 568991005  1174 PLLALTWMSAVLAVTDRR--SALFQILFAVFDSLEGFVI 1210
Cdd:pfam00002  210 PLLGITWVFGLFAFNPENtlRVVFLYLFLILNSFQGFFV 248

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 568991005  949 IVGCGVSSLTLLMLVIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLT 1028
Cdd:cd15933     9 YIGCGISIACLALTLIIFLVL-RVLSSDRFQIHKNLCVALLLAQILLLAGEWAEGNKVACKVVAILLHFFFMAAFSWMLV 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1029 EAWQSYMAVTGRLRSRLVRKRFLCLGWGLPALVVAISVGFtKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGI 1108
Cdd:cd15933    88 EGLHLYLMIVKVFNYKSKMRYYYFIGWGLPAIIVAISLAI-LFDDYGSPNVCWLSLDDGLIWAFVGPVIFIITVNTVILI 166

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1109 LVFNKLVSKDGITDKKLKERAGQLpvpplgraltcaecgvlsaaeansDATSNAMAslwsscVVLPLLALTWMSAVLAVT 1188
Cdd:cd15933   167 LVVKITVSLSTNDAKKSQGTLAQI------------------------KSTAKASV------VLLPILGLTWLFGVLVVN 216

                         250       260       270
                  ....*....|....*....|....*....|....*.
gi 568991005 1189 DRrSALFQILFAVFDSLEGFVIVMVHCILRREVQDA 1224
Cdd:cd15933   217 SQ-TIVFQYIFVILNSLQGLMIFLFHCVLNSEVRSA 251

invertebrate latrophilin-like receptors, member of the class B2 family of seven-transmembrane G protein-coupled receptors; This subgroup includes latrophilin-like proteins that are found in invertebrates such as insects and worms. Latrophilins (also called lectomedins or latrotoxin receptors) belong to Group I adhesion GPCRs, which also include 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 vertebrate 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 568991005  950 VGCGVSSLTLLMLVIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTE 1029
Cdd:cd15440    10 IGCIISIVCLLLAFITFTCF-RNLQCDRNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLAAFSWMLLE 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1030 AWQSYM---AVTGRLRSRlvRKRFLCLGWGLPALVVAISVGFtKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNmvi 1106
Cdd:cd15440    89 GFQLYVmlvEVFEPEKSR--IKWYYLFGYGLPALIVAVSAGV-DPTGYGTEDHCWLSTENGFIWSFVGPVIVVLLAN--- 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1107 giLVFnklvskdgitdkklkeragqlpvppLGRALtCAECGVLSAAEANSDATSNAMASLW--SSCVVLPLLALTWMSAV 1184
Cdd:cd15440   163 --LVF-------------------------LGMAI-YVMCRHSSRSASKKDASKLKNIRGWlkGSIVLVVLLGLTWTFGL 214

                         250       260       270
                  ....*....|....*....|....*....|....*...
gi 568991005 1185 LAVtDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQ 1222
Cdd:cd15440   215 LFI-NQESIVMAYIFTILNSLQGLFIFIFHCVLNEKVR 251

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 568991005  946 VTLIVGCGVSsLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCW 1025
Cdd:cd15441     6 IVTYIGIGIS-LVLLVIAFLVLSCLRGLQSNSNSIHKNLVACLLLAELLFLLGINQTENLFPCKLIAILLHYFYLSAFSW 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1026 VLTEAWQSYMAVTgrlRSRLVRK---RF-LCLGWGLPALVVAISVGFtKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVL 1101
Cdd:cd15441    85 LLVESLHLYRMLT---EPRDINHghmRFyYLLGYGIPAIIVGLSVGL-RPDGYGNPDFCWLSVNETLIWSFAGPIAFVIV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1102 VNMVIGILVFNKLVSKdgitdKKLKERAGQLpvpplgRALtcaecgvlsaaeansdatsnamasLWSSCVVLPLLALTWM 1181
Cdd:cd15441   161 ITLIIFILALRASCTL-----KRHVLEKASV------RTD------------------------LRSSFLLLPLLGATWV 205

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|
gi 568991005 1182 SAVLAVTDrRSALFQILFAVFDSLEGFVIVMVHCILRREV 1221
Cdd:cd15441   206 FGLLAVNE-DSELLHYLFAGLNFLQGLFIFLFYCIFNKKV 244

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 568991005  950 VGCgVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTE 1029
Cdd:cd15252    10 VGI-IISLVCLAICIFTFWFFRGLQSDRTTIHKNLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFAWMFIE 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1030 AWQSYMAVTGRLRSR-LVRKRFLCLGWGLPALVVAISVGFtKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNMV-IG 1107
Cdd:cd15252    89 GIQLYLMLVEVFENEgSRHKNFYIFGYGSPAVIVGVSAAL-GYRYYGTTKVCWLSTENYFIWSFIGPATLIILLNLIfLG 167

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568991005 1108 ILVFnklvskdgitdKKLKERAGQLPVpplgraltcaecgvlsaaeanSDATSNAMASLWSSCVVLPLLALTWMSAVLAV 1187
Cdd:cd15252   168 VAIY-----------KMFRHTAGLKPE---------------------VSCLENIRSWARGAIALLFLLGLTWIFGVLHI 215

                         250       260       270
                  ....*....|....*....|....*....|....*
gi 568991005 1188 tDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQ 1222
Cdd:cd15252   216 -NHASVVMAYLFTVSNSLQGMFIFLFHCVLSRKVR 249