seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160  939 MDKTQLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 1018
Cdd:cd15990     1 MEKALLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1019 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 1098
Cdd:cd15990    81 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1099 AVVLVNMVIGILVFNKLVSKDGITDMKLKERAGqmtvplynmtlkcakcgvisspdvsttatsnamASLWSSCVVLPLLA 1178
Cdd:cd15990   161 AVVLVNMVIGILVFNKLVSKDGITDKKLKERAG---------------------------------ASLWSSCVVLPLLA 207

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1179 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQEAVKCRVVDRQEDGN 1238
Cdd:cd15990   208 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGN 267

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 688592160   664 GVSEVMTKLRVTSSDGTSYSGDLLAIIDVLKNMTEIFRRSYYSPSNADMRNFVQSVSNLLMEENRDRWEEAQLLGPNVKE 743
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160   744 --LFRLVEDFVDVISLRMKDFQDTYEVTDNLVLSIHKRPV---AGNADITFPMKGWRGmvdwarSSEDKVRVAKNILLtg 818
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLDThnfKGARFPRFPMKGERP------KDEDSVKLPPKAFK-- 152

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 688592160   819 kpEEDDASAFVTGIVLYRNLGSILSLQRN-----------STVLNSKVISVTIKP 862
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 688592160    528 WQLWSTWSGCTKTCGGGSQQRQRLCYGP--FFGGEACPGDREEVRRCNEKRCP 578
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 688592160    242 WSGWGNWAECSSECGGGVQKRTRNCQSPPDEA--YLCEGVLEEGRPCNAQPC 291
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 688592160   886 TCISWDENDSSSllGSWSARGCRAVPVDSSTTKCLCDRLSTFAIL 930
Cdd:pfam01825    2 QCVFWDFTNSTT--GRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

brain-specific angiogenesis inhibitor 1, 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 688592160  939 MDKTQLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 1018
Cdd:cd15990     1 MEKALLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1019 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 1098
Cdd:cd15990    81 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1099 AVVLVNMVIGILVFNKLVSKDGITDMKLKERAGqmtvplynmtlkcakcgvisspdvsttatsnamASLWSSCVVLPLLA 1178
Cdd:cd15990   161 AVVLVNMVIGILVFNKLVSKDGITDKKLKERAG---------------------------------ASLWSSCVVLPLLA 207

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1179 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQEAVKCRVVDRQEDGN 1238
Cdd:cd15990   208 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGN 267

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 688592160   944 LPSVTLIVGCGVSSLTLLLLIIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNK--------VVCTLVAAF 1015
Cdd:pfam00002    3 SLKVIYTVGYSLSLVALLLAIAIFLLF-RKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKqdldhcswVGCKVVAVF 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160  1016 LHFFFLSSFCWVLTEAWQSYMA-VTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTkAKGYGTVNYCWLSLEGGLLYAFV 1094
Cdd:pfam00002   82 LHYFFLANFFWMLVEGLYLYTLlVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVD-PKGYGEDDGCWLSNENGLWWIIR 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160  1095 GPAAAVVLVNMVIGILVFNKLVSKDGITDMKLKERAgqmtvplynmtlkcakcgvisspdvsttatsNAMASLWSSCVVL 1174
Cdd:pfam00002  161 GPILLIILVNFIIFINIVRILVQKLRETNMGKSDLK-------------------------------QYRRLAKSTLLLL 209

                          250       260       270
                   ....*....|....*....|....*....|....*....
gi 688592160  1175 PLLALTWMSAVLAITDRR--SALFQILFAVFDSLEGFVI 1211
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 688592160    418 WGEWTPWSLCSSTCGRGYRERNRSCK--PPQFGGNPCDGPEKQTKFCNIAVCP 468
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 688592160    473 WNEWSGWSSCSSTCSNGTMQRIRECNGP--SYGGLECQGEWHETRDCFLRECP 523
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 688592160    242 WSGWGNWAECSSECGGGVQKRTRNCQSPPDEA--YLCEGVLEEGRPCNAQPC 291
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 688592160   886 TCISWDENDSSSllGSWSARGCRAVPVDSSTTKCLCDRLSTFAIL 930
Cdd:pfam01825    2 QCVFWDFTNSTT--GRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 688592160   243 SGWGNWAECSSECGGGVQKRTRNCQSPPDEAYLCEGVLEEGRPCNAQPC 291
Cdd:pfam00090    1 SPWSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

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

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|....*....
gi 688592160    883 TNQTCISWDENDsssllGSWSARGCRAVPVDSSTTKCLCDRLSTFAILA 931
Cdd:smart00303    1 FNPICVFWDESS-----GEWSTRGCELLETNGTHTTCSCNHLTTFAVLM 44

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 688592160   360 EWSAWSVCSATCGEGWQSRTRFCVS-VSYSTQCSGPLREQRPCN 402
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTCKSpFPGGEPCTGDDIETQACK 45

thrombosponding-related protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688592160  242 WSGWGNWAECSSECG--GGVQKRTRNCQSPPDEAYlcEGVLEEGRPCNA--QPC 291
Cdd:PTZ00087  233 YTEWGEWSNCSMECDhpDNVQIRERKCAHPSGDCF--KGDLKETRPCQVplPPC 284

brain-specific angiogenesis inhibitor 1, 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 688592160  939 MDKTQLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 1018
Cdd:cd15990     1 MEKALLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1019 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 1098
Cdd:cd15990    81 FFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAA 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1099 AVVLVNMVIGILVFNKLVSKDGITDMKLKERAGqmtvplynmtlkcakcgvisspdvsttatsnamASLWSSCVVLPLLA 1178
Cdd:cd15990   161 AVVLVNMVIGILVFNKLVSKDGITDKKLKERAG---------------------------------ASLWSSCVVLPLLA 207

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1179 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQEAVKCRVVDRQEDGN 1238
Cdd:cd15990   208 LTWMSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGN 267

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 688592160  942 TQLPSVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFL 1021
Cdd:cd15988     1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1022 SSFCWVLTEAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVV 1101
Cdd:cd15988    81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1102 LVNMVIGILVFNKLVSKDGITDMKLKERAGQMTVPLYNMTLKCAKCGVISSPDVSTTATSNAMASLWSSCVVLPLLALTW 1181
Cdd:cd15988   161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGSEAEPCSSLLLKCSKCGVVSSAAMSSATASSAMASLWSSCVVLPLLALTW 240

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....*....
gi 688592160 1182 MSAVLAITDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQEAVKCRV 1230
Cdd:cd15988   241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQM 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 688592160    37 DSCSTLVQSRFFGFFLSSSAFPSMP--CTWTLQNPDPRRYTIFIKVTKPTRDCIARQHRTFQFDSFLET-TRTFLGMESF 113
Cdd:pfam19188    1 DPCSTLVQGVLYGSFSLRDLFPTNAsgCSWTLENPDPTKYTLYLKFTKPTQSCLPFSPRLLQFDHYLENtTRTYLGRESF 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160   114 DEVVKLCDASTHVAFLEAGKQFLQIRKGLPRAGA---GSRNGDGEFKVEYLVVGKRNPSMAACQMLCQWLEDCLTYSSST 190
Cdd:pfam19188   81 DEVVELCDASSPFSFLEFDKNFVQLCLLAEPRGDpesVVPGPSGDFKVEVLVINNENPSQFTCGVLCRWLEECLSASTSS 160

                          170
                   ....*....|....*..
gi 688592160   191 RPCGIMQTPCQCWDQPP 207
Cdd:pfam19188  161 RPCGIMQTPCICPGTVP 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 688592160  946 SVTLIVGCGVSSLTLLLLIIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFC 1025
Cdd:cd15040     5 SIITYIGCGLSLLGLLLTIITYILFRKLRKRKPTKILLNLCLALLLANLLFLFGINSTDNPVLCTAVAALLHYFLLASFM 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1026 WVLTEAWQSYMAVTG--RLRNRIIRKRFLCLGWGLPALVVAISVGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLV 1103
Cdd:cd15040    85 WMLVEALLLYLRLVKvfGTYPRHFILKYALIGWGLPLIIVIITLAVDPDSYGNSSGYCWLSNGNGLYYAFLGPVLLIILV 164

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1104 NMVIGILVFNKLVSKDGITDMKLKeragqmtvplynmtlkcakcgvisspdvsttatSNAMASLWSSCVVLPLLALTWMS 1183
Cdd:cd15040   165 NLVIFVLVLRKLLRLSAKRNKKKR---------------------------------KKTKAQLRAAVSLFFLLGLTWIF 211

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|...
gi 688592160 1184 AVLAITDRRSAlFQILFAVFDSLEGFVIVMVHCILRREVQEAV 1226
Cdd:cd15040   212 GILAIFGARVV-FQYLFAIFNSLQGFFIFIFHCLRNKEVRKAW 253

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 688592160  950 IVGCGVSSLTLLLLIIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLT 1029
Cdd:cd15933     9 YIGCGISIACLALTLIIFLVL-RVLSSDRFQIHKNLCVALLLAQILLLAGEWAEGNKVACKVVAILLHFFFMAAFSWMLV 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1030 EAWQSYMAVTGRLRNRIIRKRFLCLGWGLPALVVAISVGFtKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGI 1109
Cdd:cd15933    88 EGLHLYLMIVKVFNYKSKMRYYYFIGWGLPAIIVAISLAI-LFDDYGSPNVCWLSLDDGLIWAFVGPVIFIITVNTVILI 166

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1110 LVfnklvskdgitdmkLKERAGQMTVPLYNMTLKCAkcgVISSpdvsttaTSNAMAslwsscVVLPLLALTWMSAVLAIT 1189
Cdd:cd15933   167 LV--------------VKITVSLSTNDAKKSQGTLA---QIKS-------TAKASV------VLLPILGLTWLFGVLVVN 216

                         250       260       270
                  ....*....|....*....|....*....|....*.
gi 688592160 1190 DrRSALFQILFAVFDSLEGFVIVMVHCILRREVQEA 1225
Cdd:cd15933   217 S-QTIVFQYIFVILNSLQGLMIFLFHCVLNSEVRSA 251

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 688592160  972 RYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAVTGRLRNRIIRKRF 1051
Cdd:cd15438    30 RSIRGTRNTIHLHLCLSLFLAHLIFLLGINNTNNQVACAVVAGLLHYFFLAAFCWMSLEGVELYLMVVQVFNTQSLKKRY 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1052 LCL-GWGLPALVVAISVGfTKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILVFNKLVSK--DGITDMKLKE 1128
Cdd:cd15438   110 LLLiGYGVPLVIVAISAA-VNSKGYGTQRHCWLSLERGFLWSFLGPVCLIILVNAIIFVITVWKLAEKfsSINPDMEKLR 188

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1129 RAGQMTVplynmtlkcakcgvisspdvsttatsNAMASLWsscvvlpLLALTWMSAVLAITDrRSALFQILFAVFDSLEG 1208
Cdd:cd15438   189 KIRALTI--------------------------TAIAQLC-------ILGCTWIFGFFQFSD-STLVMSYLFTILNSLQG 234

                         250
                  ....*....|....*.
gi 688592160 1209 FVIVMVHCILRREVQE 1224
Cdd:cd15438   235 LFIFLLHCLLSKQVRE 250

epidermal growth factor-like module-containing mucin-like hormone receptors, member of the class B2 family of seven-transmembrane G protein-coupled receptors; group II adhesion GPCRs, including the epidermal growth factor (EGF)-module-containing, mucin-like hormone receptor (EMR1-4) and the leukocyte cell-surface antigen CD97, are primarily expressed in cells of the immune system. All EGF-TM7 receptors, which belong to the B2 subfamily 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 number 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 EMR2, alternative splicing results in four isoforms possessing either two (EGF1,2), 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. EMR2 shares strong sequence homology with CD97, differing by only six amino acids. 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. 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 688592160  972 RYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAVtgrlRN------- 1044
Cdd:cd15439    30 RSIRNTSTSLHLQLSLCLFLADLLFLVGIDRTDNKVLCSIIAGFLHYLFLACFAWMFLEAVHLFLTV----RNlkvvnyf 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1045 --RIIRKRFLCL-GWGLPALVVAISVGfTKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILVF----NKLVS 1117
Cdd:cd15439   106 ssHRFKKRFMYPvGYGLPAVIVAISAA-VNPQGYGTPKHCWLSMEKGFIWSFLGPVCVIIVINLVLFCLTLwilrEKLSS 184

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1118 KDG-ITDMKlKERAgqmtvplynMTLKcakcgvisspdvsttatsnAMASLWsscvvlpLLALTWMSAVLAITDRRSALf 1196
Cdd:cd15439   185 LNAeVSTLK-NTRL---------LTFK-------------------AIAQLF-------ILGCTWILGLFQVGPVATVM- 227

                         250       260       270
                  ....*....|....*....|....*....|.
gi 688592160 1197 QILFAVFDSLEGFVIVMVHCILRREVQEAVK 1227
Cdd:cd15439   228 AYLFTITNSLQGVFIFLVHCLLNRQVREEYR 258

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 688592160  951 VGCGVSSLTLLLLIIIYVSVwRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTE 1030
Cdd:cd15440    10 IGCIISIVCLLLAFITFTCF-RNLQCDRNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLAAFSWMLLE 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1031 AWQSYM---AVTGRLRNRIirKRFLCLGWGLPALVVAISVGFtKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLVNmvi 1107
Cdd:cd15440    89 GFQLYVmlvEVFEPEKSRI--KWYYLFGYGLPALIVAVSAGV-DPTGYGTEDHCWLSTENGFIWSFVGPVIVVLLAN--- 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1108 giLVFnklvskdgitdmklkeragqMTVPLYNMtlkcakCGVISSPDVSTTATSNAMASLW--SSCVVLPLLALTWMSAV 1185
Cdd:cd15440   163 --LVF--------------------LGMAIYVM------CRHSSRSASKKDASKLKNIRGWlkGSIVLVVLLGLTWTFGL 214

                         250       260       270
                  ....*....|....*....|....*....|....*...
gi 688592160 1186 LAItDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQ 1223
Cdd:cd15440   215 LFI-NQESIVMAYIFTILNSLQGLFIFIFHCVLNEKVR 251

EGF-like module receptors, group II adhesion GPCRs, member of 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. On the other hand, EMR2 generates four isoforms possessing either two (EGF1,2), 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 688592160  972 RYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAV-----TGRLRNRI 1046
Cdd:cd15931    30 RWIPKINTTAHLHLCLCLSMSHTLFLAGIEYVENELACTVMAGLLHYLFLASFVWMLLEALQLHLLVrrltkVQVIQRDG 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688592160 1047 IRKRFLCL-GWGLPALVVAISvGFTKAKGYGTVNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILvfnklvskdgiTDMK 1125
Cdd:cd15931   110 LPRPLLCLiGYGVPFLIVGVS-ALVYSDGYGEAKMCWLSQERGFNWSFLGPVIAIIGINWILFCA-----------TLWC 177