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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 296317300   529 TVRCVFWDlgrnGGRGGWSDNGCSVKDRRLNETICTCSHLTSFGVLLDLSR 579
Cdd:smart00303   2 NPICVFWD----ESSGEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPP 48

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 296317300  587 MMALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDyPSKILIQLCAALLLLNLVFLLDSWIALYKMQG------LCISVA 660
Cdd:pfam00002   1 ALSLKVIYTVGYSLSLVALLLAIAIFLLFRKLHCT-RNYIHLNLFASFILRALLFLVGDAVLFNKQDLdhcswvGCKVVA 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300  661 VFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYiRKYILKFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFC 740
Cdd:pfam00002  80 VFLHYFFLANFFWMLVEGLYLYTLLVEVFFSE-RKYFWWYLLIGWGVPALVVGIWAGVDPKGYG-----------EDDGC 147

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300  741 WINNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSI-QDLRSIAGLTFLLGITWGFAFFAWGPVN 819
Cdd:pfam00002 148 WLSNENGLWWIIRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDLKQYrRLAKSTLLLLPLLGITWVFGLFAFNPEN 227

                         250       260
                  ....*....|....*....|.
gi 296317300  820 ---VTFMYLFAIFNTLQGFFI 837
Cdd:pfam00002 228 tlrVVFLYLFLILNSFQGFFV 248

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 296317300  530 VRCVFWDLGrNGGRGGWSDNGCSVKDRRLNETICTCSHLTSFGVL 574
Cdd:pfam01825   1 PQCVFWDFT-NSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Spumavirus gag protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300  211 HPRGPPFSSSQSIPVvPRATVL-SQVPKATSFAEPPDYSPVTHNVPsPIGEIQPLSP----------QPSAPIASSPAID 279
Cdd:pfam03276 205 HLPAIPGIHARAPPG-NIARSLgDDIMPSLGDAGMPQPRFAFHPGN-PFAEAEGHPFaeaegerprdIPRAPRIDAPSAP 282

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300  280 MPPQSETISSPMPQTHVSGTPPPVKASFSSPTVSAPANV---NTTSAP------PVQTDIVNTSSISDLENQVLQMEKAL 350
Cdd:pfam03276 283 AIPAIQPIAPPMIPPIGAPIPIPHGASIPGEHIRNPREEpirLGREAPaidgrfAPAIDDLFCRIINALLCGIIGALLGG 362

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|...
gi 296317300  351 SLG-SLEPNLAGEMINQVSRL-LHSPPDMLAPLAQRLLK-VVDDIGLQLNFSN 400
Cdd:pfam03276 363 GDCiSLDPADAILFDRAVAQLfIHQLGNVLKGIADNEGKaIADQEGMALAGQL 415

orphan GPR126 and related proteins, group VIII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Group VIII adhesion GPCRs include orphan GPCRs such as GPR56, GPR64, GPR97, GPR112, GPR114, and GPR126. GPR56 is involved in the regulation of oligodendrocyte development and myelination in the central nervous system via coupling to G(12/13) proteins, which leads to the activation of RhoA GTPase. GPR126, on the other hand, is required for Schwann cells, but not oligodendrocyte myelination in the peripheral nervous system. Gpr64 is mainly expressed in the epididymis of male reproductive tract, and targeted deletion of GPR64 causes sperm stasis and efferent duct blockage due to abnormal fluid reabsorption, resulting in male infertility. GPR64 is also over-expressed in Ewing's sarcoma (ES), as well as upregulated in other carcinomas from kidney, prostate or lung, and promotes invasiveness and metastasis in ES via the upregulation of placental growth factor (PGF) and matrix metalloproteinase (MMP) 1. GPR97 is identified as a lymphatic adhesion receptor that is specifically expressed in lymphatic endothelium, but not in blood vascular endothelium, and is shown to regulate migration of lymphatic endothelial cells via the small GTPases RhoA and cdc42. GPR112 is specifically expressed in normal enterochromatin cells and gastrointestinal neuroendocrine carcinoma cells, but its biological function is unknown. GPR114 is mainly found in granulocytes (polymorphonuclear leukocytes), and GPR114-transfected cells induced an increase in cAMP levels via coupling to G(s) protein. 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. 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 296317300 587 MMALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYF 666
Cdd:cd15258    1 LHILTFISYVGCGISAIFLAITILTYIAFRKLRRDYPSKIHMNLCAALLLLNLAFLLSSWIASFGSDGLCIAVAVALHYF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 667 LLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGSPDDFCWINNNA 746
Cdd:cd15258   81 LLACLTWMGLEAFHLYLLLVKVFNTYIRRYILKLCLVGWGLPALLVTLVLSVRSDNYGPITIPNGEGFQNDSFCWIRDPV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 747 VFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLgAQRKTSIQDLRSIAGLTFLLGITWGFAFFAWGPVNVTFMYLF 826
Cdd:cd15258  161 VFYITVVGYFGLTFLFNMVMLATVLVQICRLREKAQA-TPRKRALHDLLTLLGLTFLLGLTWGLAFFAWGPFNLPFLYLF 239

                        250       260
                 ....*....|....*....|....*...
gi 296317300 827 AIFNTLQGFFIFIFYCVAKENVRKQWRR 854
Cdd:cd15258  240 AIFNSLQGFFIFIWYCSMKENVRKQWRA 267

orphan adhesion receptor GPR126, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR126 is an orphan receptor that has been classified as that belongs to the Group VIII of adhesion GPCRs. Other members of the Group VII include orphan GPCRs such as GPR56, GPR64, GPR97, GPR112, and GPR114. GPR126 is required in Schwann cells for proper differentiation and myelination via G-Protein Activation. GPR126 is believed to couple to G(s)-protein, which leads to activation of adenylate cyclase for cAMP production. 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. 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 296317300 590 LTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLLV 669
Cdd:cd15996    4 LTFITYIGCGISAIFSAATLLTYIAFEKLRRDYPSKILMNLSTALLFLNLVFLLDGWIASFEIDELCITVAVLLHFFLLA 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 670 SFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGSP-DDFCWINNNAVF 748
Cdd:cd15996   84 TFTWMGLEAIHMYIALVKVFNTYIRRYILKFCIIGWGLPALIVSIVLASTNDNYGYGYYGKDKDGQGgDEFCWIKNPVVF 163

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 749 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGITWGFAFFAWGPVNVTFMYLFAI 828
Cdd:cd15996  164 YVTCAAYFGIMFLMNVAMFIVVMVQICGRNGKRSNRTLREEILRNLRSVVSLTFLLGMTWGFAFFAWGPVNLAFMYLFTI 243

                        250       260
                 ....*....|....*....|....*...
gi 296317300 829 FNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd15996  244 FNSLQGLFIFVFHCALKENVQKQWRRHL 271

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 589 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRdYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLL 668
Cdd:cd13952    3 ALSIITYIGCSLSLVGLLLTIITYLLFPKLRN-LRGKILINLCLSLLLAQLLFLIGQLLTSSDRPVLCKALAILLHYFLL 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 669 VSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKfpngspDDFCWINNNAVF 748
Cdd:cd13952   82 ASFFWMLVEAFDLYRTFVKVFGSSERRRFLKYSLYGWGLPLLIVIITAIVDFSLYGPSPGYG------GEYCWLSNGNAL 155

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 749 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGITWGFAFFAW-GPVNVTFMYLFA 827
Cdd:cd13952  156 LWAFYGPVLLILLVNLVFFILTVRILLRKLRETPKQSERKSDRKQLRAYLKLFPLMGLTWIFGILAPfVGGSLVFWYLFD 235

                        250       260
                 ....*....|....*....|....*
gi 296317300 828 IFNTLQGFFIFIFYCVAKENVRKQW 852
Cdd:cd13952  236 ILNSLQGFFIFLIFCLKNKEVRRLL 260

orphan adhesion receptor GPR97, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR97 is an orphan receptor that has been classified into the group VIII of adhesion GPCRs. Other members of the Group VII include GPR56, GPR64, GPR112, GPR114, and GPR126. GPR97 is identified as a lymphatic adhesion receptor that is specifically expressed in lymphatic endothelium, but not in blood vascular endothelium, and is shown to regulate migration of lymphatic endothelial cells via the small GTPases RhoA and cdc42. 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. 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 296317300 590 LTFITYIGCGLSSIFLSVTLVTYIA----FEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHY 665
Cdd:cd15442    4 LVTISSAGCGVSMVFLIFTIILYFFlrftYQKFKSEDAPKIHVNLSSSLLLLNLAFLLNSGVSSRAHPGLCKALGGVTHY 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 666 FLLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIilTISPDNYGLGSYGKFPNGSPDDFCWINNN 745
Cdd:cd15442   84 FLLCCFTWMAIEAFHLYLLAIKVFNTYIHHYFAKLCLVGWGFPALVVTI--TGSINSYGAYTIMDMANRTTLHLCWINSK 161

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 746 A--VFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLrSIAGLTFLLGITWGFAFFAWGPVNVTFM 823
Cdd:cd15442  162 HltVHYITVCGYFGLTFLFNTVVLGLVAWKIFHLQSATAGKEKCQAWKGGL-TVLGLSCLLGVTWGLAFFTYGSMSVPTV 240

                        250       260
                 ....*....|....*....|
gi 296317300 824 YLFAIFNTLQGFFIFIFYCV 843
Cdd:cd15442  241 YIFALLNSLQGLFIFIWFVI 260

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 296317300 589 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDypsKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLL 668
Cdd:cd15440    3 ALTFITYIGCIISIVCLLLAFITFTCFRNLQCD---RNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFL 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 669 VSFTWMGLEAFHMYLALVKVFNTYIRKyILKFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCWINNNAVF 748
Cdd:cd15440   80 AAFSWMLLEGFQLYVMLVEVFEPEKSR-IKWYYLFGYGLPALIVAVSAGVDPTGYG-----------TEDHCWLSTENGF 147

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 749 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKK--KKQLGAQRKTSIQD-LRSIAGLTFLLGITWGFAFFAWGPVNVTFMYL 825
Cdd:cd15440  148 IWSFVGPVIVVLLANLVFLGMAIYVMCRHSSrsASKKDASKLKNIRGwLKGSIVLVVLLGLTWTFGLLFINQESIVMAYI 227

                        250       260       270
                 ....*....|....*....|....*....|.
gi 296317300 826 FAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd15440  228 FTILNSLQGLFIFIFHCVLNEKVRKELRRWL 258

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 296317300 588 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYpSKILIQLCAALLLLNLVFLLDSWIALYKMqgLCISVAVFLHYFL 667
Cdd:cd15933    2 RALSIISYIGCGISIACLALTLIIFLVLRVLSSDR-FQIHKNLCVALLLAQILLLAGEWAEGNKV--ACKVVAILLHFFF 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 668 LVSFTWMGLEAFHMYLALVKVFNTYIRKYIlkFCIVGWGVPAVVVTIILTISPDNYGLgsygkfpngspDDFCW--INNN 745
Cdd:cd15933   79 MAAFSWMLVEGLHLYLMIVKVFNYKSKMRY--YYFIGWGLPAIIVAISLAILFDDYGS-----------PNVCWlsLDDG 145

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 746 AVFYITVVgyfcVIFLLNVSMFIVVLV-----QLCRIKKKKQLG--AQRKTSIqdlRSIAGLTFLLGITWGFAFFAWGPV 818
Cdd:cd15933  146 LIWAFVGP----VIFIITVNTVILILVvkitvSLSTNDAKKSQGtlAQIKSTA---KASVVLLPILGLTWLFGVLVVNSQ 218

                        250       260       270
                 ....*....|....*....|....*....|....
gi 296317300 819 NVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQW 852
Cdd:cd15933  219 TIVFQYIFVILNSLQGLMIFLFHCVLNSEVRSAF 252

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 296317300 589 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLdswIALYKMQGLCISVAVFLHYFLL 668
Cdd:cd15439    3 ALTVITYVGLIISLLCLFLAILTFLLCRSIRNTSTSLHLQLSLCLFLADLLFLVG---IDRTDNKVLCSIIAGFLHYLFL 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 669 VSFTWMGLEAFHMYLAL--VKVFN-TYIRKYILKF-CIVGWGVPAVVVTIILTISPDNYGLGSYgkfpngspddfCWINN 744
Cdd:cd15439   80 ACFAWMFLEAVHLFLTVrnLKVVNyFSSHRFKKRFmYPVGYGLPAVIVAISAAVNPQGYGTPKH-----------CWLSM 148

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 745 NAVFYITVVGYFCVIFLLNVSMFIVVLVQLcriKKK-----KQLGAQRKTSIQDLRSIAGLtFLLGITWGFAFFAWGPVN 819
Cdd:cd15439  149 EKGFIWSFLGPVCVIIVINLVLFCLTLWIL---REKlsslnAEVSTLKNTRLLTFKAIAQL-FILGCTWILGLFQVGPVA 224

                        250       260       270
                 ....*....|....*....|....*....|....*....
gi 296317300 820 VTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYLCC 858
Cdd:cd15439  225 TVMAYLFTITNSLQGVFIFLVHCLLNRQVREEYRRWITG 263

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 296317300 588 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRD----YPSKILIQLCAALLLLNLVFLLDSWIAlykmqglCISVAVFL 663
Cdd:cd15252    2 NILTRITQVGIIISLVCLAICIFTFWFFRGLQSDrttiHKNLCISLFLAELVFLIGINTTTNKIF-------CSVIAGLL 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 664 HYFLLVSFTWMGLEAFHMYLALVKVFNT--YIRKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCW 741
Cdd:cd15252   75 HYFFLAAFAWMFIEGIQLYLMLVEVFENegSRHKN---FYIFGYGSPAVIVGVSAALGYRYYG-----------TTKVCW 140

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 742 INNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQD-LRSIAGLTFLLGITWGFAFFAWGPVNV 820
Cdd:cd15252  141 LSTENYFIWSFIGPATLIILLNLIFLGVAIYKMFRHTAGLKPEVSCLENIRSwARGAIALLFLLGLTWIFGVLHINHASV 220

                        250       260       270
                 ....*....|....*....|....*....|....*.
gi 296317300 821 TFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd15252  221 VMAYLFTVSNSLQGMFIFLFHCVLSRKVRKEYYKLF 256

orphan adhesion receptor GPR128, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR128 is an orphan receptor of the adhesion family (subclass B2) that belongs to the class B GPCRs. Expression of GPR128 was detected in the mouse intestinal mucosa and is thought to be involved in energy balance, as its knockout mice showed a decrease in body weight gain and an increase in intestinal contraction frequency compared to wild-type controls. 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. 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 296317300 589 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKI-----------------------LIQLCAALLLLNLVFLLDS 645
Cdd:cd15257    3 TLDIISTIGCVLSIAGLVITIIFHLHTRKLRKSSVTWVllnlcsslllfniiftsgventnNDYEISTVPDRETNTVLLS 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 646 WIALYKMQGLCISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTIS---PDN 722
Cdd:cd15257   83 EEYVEPDTDVCTAVAALLHYFLLVTFMWNAVYSAQLYLLLIRMMKPLPEMFILQASAIGWGIPAVVVAITLGATyrfPTS 162

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 723 YGLGSYGKfpngSPDDFCWIN--------NNAVFY--ITVVGyfcVIFLLNVSMFIVVLVQLCriKKKKQLGAQRKTSIQ 792
Cdd:cd15257  163 LPVFTRTY----RQEEFCWLAaldknfdiKKPLLWgfLLPVG---LILITNVILFIMTSQKVL--KKNNKKLTTKKRSYM 233

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 296317300 793 DLRSIA-GLTFLLGITWGFAFFAW---GPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRK 850
Cdd:cd15257  234 KKIYITvSVAVVFGITWILGYLMLvnnDLSKLVFSYIFCITNTTQGVQIFILYTWRTPEFRK 295

Latrophilin-1, member of the class B2 family of seven-transmembrane G protein-coupled receptors; 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 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 296317300 656 CISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNT-YIRKYILKFCivGWGVPAVVVTIILTISPDNYGlgsygkfpng 734
Cdd:cd16007   67 CPIFAGLLHFFFLAAFSWLCLEGVQLYLMLVEVFESeYSRKKYYYLC--GYCFPALVVGISAAIDYRSYG---------- 134

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 735 sPDDFCWINNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQD--LRSIAgLTFLLGITWGFAF 812
Cdd:cd16007  135 -TEKACWLRVDNYFIWSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSwaLGAIT-LLFLLGLTWAFGL 212

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 296317300 813 FAWGPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd16007  213 LFINKESVVMAYLFTTFNAFQGMFIFIFHCALQKKVHKEYSKCL 256

Latrophilin-3, member of the class B2 family of seven-transmembrane G protein-coupled receptors; 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 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 296317300 588 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRD----YPSKILIQLCAALLLLNLVFLLDSWIAlykmqglCISVAVFL 663
Cdd:cd16005    2 LLLDVITWVGILLSLVCLLICIFTFCFFRGLQSDrntiHKNLCISLFVAELLFLIGINRTDQPIA-------CAVFAALL 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 664 HYFLLVSFTWMGLEAFHMYLALVKVFNT--YIRKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCW 741
Cdd:cd16005   75 HFFFLAAFTWMFLEGVQLYIMLVEVFESehSRRKY---FYLVGYGMPALIVAVSAAVDYRSYG-----------TDKVCW 140

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 742 INNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKK--KKQLGAQRKTSIQDLRSIAgLTFLLGITWGFAFFAWGPVN 819
Cdd:cd16005  141 LRLDTYFIWSFIGPATLIIMLNVIFLGIALYKMFHHTAilKPESGCLDNIKSWVIGAIA-LLCLLGLTWAFGLMYINEST 219

                        250       260       270
                 ....*....|....*....|....*....|....*..
gi 296317300 820 VTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd16005  220 VIMAYLFTIFNSLQGMFIFIFHCVLQKKVRKEYGKCL 256

Latrophilins, member of the class B2 family of seven-transmembrane G protein-coupled receptors; 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 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 296317300 656 CISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYI--RKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpn 733
Cdd:cd15436   67 CPIFAGLLHFFFLAAFCWLCLEGVQLYLLLVEVFESEYsrRKY---FYLCGYSFPALVVAVSAAIDYRSYG--------- 134

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296317300 734 gsPDDFCWINNNAVFYITVVGYFCVIFLLNVsmfIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIA----GLTFLLGITWG 809
Cdd:cd15436  135 --TEKACWLRVDNYFIWSFIGPVTFVITLNL---VFLVITLHKMVSHSDLLKPDSSRLDNIKSWAlgaiALLFLLGLTWS 209

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 296317300 810 FAFFAWGPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 856
Cdd:cd15436  210 FGLMFINEESVVMAYLFTIFNAFQGVFIFIFHCALQKKVRKEYSKCL 256