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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|.
gi 768031887    567 TVRCVFWDlgrnGGRGGWSDNGCSVKDRRLNETICTCSHLTSFGVLLDLSR 617
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 768031887   625 MMALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDyPSKILIQLCAALLLLNLVFLLDSWIALYKMQG------LCISVA 698
Cdd:pfam00002    1 ALSLKVIYTVGYSLSLVALLLAIAIFLLFRKLHCT-RNYIHLNLFASFILRALLFLVGDAVLFNKQDLdhcswvGCKVVA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887   699 VFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYiRKYILKFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFC 778
Cdd:pfam00002   80 VFLHYFFLANFFWMLVEGLYLYTLLVEVFFSE-RKYFWWYLLIGWGVPALVVGIWAGVDPKGYG-----------EDDGC 147

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887   779 WINNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSI-QDLRSIAGLTFLLGITWGFAFFAWGPVN 857
Cdd:pfam00002  148 WLSNENGLWWIIRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDLKQYrRLAKSTLLLLPLLGITWVFGLFAFNPEN 227

                          250       260
                   ....*....|....*....|.
gi 768031887   858 ---VTFMYLFAIFNTLQGFFI 875
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 768031887   568 VRCVFWDLGrNGGRGGWSDNGCSVKDRRLNETICTCSHLTSFGVL 612
Cdd:pfam01825    1 PQCVFWDFT-NSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Spumavirus gag protein;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887   249 HPRGPPFSSSQSIPVvPRATVL-SQVPKATSFAEPPDYSPVTHNVPsPIGEIQPLSP----------QPSAPIASSPAID 317
Cdd:pfam03276  205 HLPAIPGIHARAPPG-NIARSLgDDIMPSLGDAGMPQPRFAFHPGN-PFAEAEGHPFaeaegerprdIPRAPRIDAPSAP 282

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887   318 MPPQSETISSPMPQTHVSGTPPPVKASFSSPTVSAPANV---NTTSAP------PVQTDIVNTSSISDLENQVLQMEKAL 388
Cdd:pfam03276  283 AIPAIQPIAPPMIPPIGAPIPIPHGASIPGEHIRNPREEpirLGREAPaidgrfAPAIDDLFCRIINALLCGIIGALLGG 362

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|...
gi 768031887   389 SLG-SLEPNLAGEMINQVSRL-LHSPPDMLAPLAQRLLK-VVDDIGLQLNFSN 438
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 768031887  625 MMALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYF 704
Cdd:cd15258     1 LHILTFISYVGCGISAIFLAITILTYIAFRKLRRDYPSKIHMNLCAALLLLNLAFLLSSWIASFGSDGLCIAVAVALHYF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  705 LLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGSPDDFCWINNNA 784
Cdd:cd15258    81 LLACLTWMGLEAFHLYLLLVKVFNTYIRRYILKLCLVGWGLPALLVTLVLSVRSDNYGPITIPNGEGFQNDSFCWIRDPV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  785 VFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLgAQRKTSIQDLRSIAGLTFLLGITWGFAFFAWGPVNVTFMYLF 864
Cdd:cd15258   161 VFYITVVGYFGLTFLFNMVMLATVLVQICRLREKAQA-TPRKRALHDLLTLLGLTFLLGLTWGLAFFAWGPFNLPFLYLF 239

                         250       260
                  ....*....|....*....|....*...
gi 768031887  865 AIFNTLQGFFIFIFYCVAKENVRKQWRR 892
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 768031887  628 LTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLLV 707
Cdd:cd15996     4 LTFITYIGCGISAIFSAATLLTYIAFEKLRRDYPSKILMNLSTALLFLNLVFLLDGWIASFEIDELCITVAVLLHFFLLA 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  708 SFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGS-PDDFCWINNNAVF 786
Cdd:cd15996    84 TFTWMGLEAIHMYIALVKVFNTYIRRYILKFCIIGWGLPALIVSIVLASTNDNYGYGYYGKDKDGQgGDEFCWIKNPVVF 163

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  787 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGITWGFAFFAWGPVNVTFMYLFAI 866
Cdd:cd15996   164 YVTCAAYFGIMFLMNVAMFIVVMVQICGRNGKRSNRTLREEILRNLRSVVSLTFLLGMTWGFAFFAWGPVNLAFMYLFTI 243

                         250       260
                  ....*....|....*....|....*...
gi 768031887  867 FNTLQGFFIFIFYCVAKENVRKQWRRYL 894
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 768031887  627 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRdYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLL 706
Cdd:cd13952     3 ALSIITYIGCSLSLVGLLLTIITYLLFPKLRN-LRGKILINLCLSLLLAQLLFLIGQLLTSSDRPVLCKALAILLHYFLL 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  707 VSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKfpngspDDFCWINNNAVF 786
Cdd:cd13952    82 ASFFWMLVEAFDLYRTFVKVFGSSERRRFLKYSLYGWGLPLLIVIITAIVDFSLYGPSPGYG------GEYCWLSNGNAL 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  787 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGITWGFAFFAW-GPVNVTFMYLFA 865
Cdd:cd13952   156 LWAFYGPVLLILLVNLVFFILTVRILLRKLRETPKQSERKSDRKQLRAYLKLFPLMGLTWIFGILAPfVGGSLVFWYLFD 235

                         250       260
                  ....*....|....*....|....*
gi 768031887  866 IFNTLQGFFIFIFYCVAKENVRKQW 890
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 768031887  628 LTFITYIGCGLSSIFLSVTLVTYIA----FEKIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHY 703
Cdd:cd15442     4 LVTISSAGCGVSMVFLIFTIILYFFlrftYQKFKSEDAPKIHVNLSSSLLLLNLAFLLNSGVSSRAHPGLCKALGGVTHY 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  704 FLLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIilTISPDNYGLGSYGKFPNGSPDDFCWINNN 783
Cdd:cd15442    84 FLLCCFTWMAIEAFHLYLLAIKVFNTYIHHYFAKLCLVGWGFPALVVTI--TGSINSYGAYTIMDMANRTTLHLCWINSK 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  784 A--VFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLrSIAGLTFLLGITWGFAFFAWGPVNVTFM 861
Cdd:cd15442   162 HltVHYITVCGYFGLTFLFNTVVLGLVAWKIFHLQSATAGKEKCQAWKGGL-TVLGLSCLLGVTWGLAFFTYGSMSVPTV 240

                         250       260
                  ....*....|....*....|
gi 768031887  862 YLFAIFNTLQGFFIFIFYCV 881
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 768031887  627 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDypsKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLL 706
Cdd:cd15440     3 ALTFITYIGCIISIVCLLLAFITFTCFRNLQCD---RNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  707 VSFTWMGLEAFHMYLALVKVFNTYIRKyILKFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCWINNNAVF 786
Cdd:cd15440    80 AAFSWMLLEGFQLYVMLVEVFEPEKSR-IKWYYLFGYGLPALIVAVSAGVDPTGYG-----------TEDHCWLSTENGF 147

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  787 YITVVGYFCVIFLLNVSMFIVVLVQLCRIKK--KKQLGAQRKTSIQD-LRSIAGLTFLLGITWGFAFFAWGPVNVTFMYL 863
Cdd:cd15440   148 IWSFVGPVIVVLLANLVFLGMAIYVMCRHSSrsASKKDASKLKNIRGwLKGSIVLVVLLGLTWTFGLLFINQESIVMAYI 227

                         250       260       270
                  ....*....|....*....|....*....|.
gi 768031887  864 FAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 894
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 768031887  626 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYpSKILIQLCAALLLLNLVFLLDSWIALYKMqgLCISVAVFLHYFL 705
Cdd:cd15933     2 RALSIISYIGCGISIACLALTLIIFLVLRVLSSDR-FQIHKNLCVALLLAQILLLAGEWAEGNKV--ACKVVAILLHFFF 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  706 LVSFTWMGLEAFHMYLALVKVFNTYIRKYIlkFCIVGWGVPAVVVTIILTISPDNYGLgsygkfpngspDDFCW--INNN 783
Cdd:cd15933    79 MAAFSWMLVEGLHLYLMIVKVFNYKSKMRY--YYFIGWGLPAIIVAISLAILFDDYGS-----------PNVCWlsLDDG 145

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  784 AVFYITVVgyfcVIFLLNVSMFIVVLV-----QLCRIKKKKQLG--AQRKTSIqdlRSIAGLTFLLGITWGFAFFAWGPV 856
Cdd:cd15933   146 LIWAFVGP----VIFIITVNTVILILVvkitvSLSTNDAKKSQGtlAQIKSTA---KASVVLLPILGLTWLFGVLVVNSQ 218

                         250       260       270
                  ....*....|....*....|....*....|....
gi 768031887  857 NVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQW 890
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 768031887  627 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKILIQLCAALLLLNLVFLLdswIALYKMQGLCISVAVFLHYFLL 706
Cdd:cd15439     3 ALTVITYVGLIISLLCLFLAILTFLLCRSIRNTSTSLHLQLSLCLFLADLLFLVG---IDRTDNKVLCSIIAGFLHYLFL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  707 VSFTWMGLEAFHMYLAL--VKVFN-TYIRKYILKF-CIVGWGVPAVVVTIILTISPDNYGLGSYgkfpngspddfCWINN 782
Cdd:cd15439    80 ACFAWMFLEAVHLFLTVrnLKVVNyFSSHRFKKRFmYPVGYGLPAVIVAISAAVNPQGYGTPKH-----------CWLSM 148

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  783 NAVFYITVVGYFCVIFLLNVSMFIVVLVQLcriKKK-----KQLGAQRKTSIQDLRSIAGLtFLLGITWGFAFFAWGPVN 857
Cdd:cd15439   149 EKGFIWSFLGPVCVIIVINLVLFCLTLWIL---REKlsslnAEVSTLKNTRLLTFKAIAQL-FILGCTWILGLFQVGPVA 224

                         250       260       270
                  ....*....|....*....|....*....|....*....
gi 768031887  858 VTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYLCC 896
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 768031887  626 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRD----YPSKILIQLCAALLLLNLVFLLDSWIAlykmqglCISVAVFL 701
Cdd:cd15252     2 NILTRITQVGIIISLVCLAICIFTFWFFRGLQSDrttiHKNLCISLFLAELVFLIGINTTTNKIF-------CSVIAGLL 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  702 HYFLLVSFTWMGLEAFHMYLALVKVFNT--YIRKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCW 779
Cdd:cd15252    75 HYFFLAAFAWMFIEGIQLYLMLVEVFENegSRHKN---FYIFGYGSPAVIVGVSAALGYRYYG-----------TTKVCW 140

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  780 INNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQD-LRSIAGLTFLLGITWGFAFFAWGPVNV 858
Cdd:cd15252   141 LSTENYFIWSFIGPATLIILLNLIFLGVAIYKMFRHTAGLKPEVSCLENIRSwARGAIALLFLLGLTWIFGVLHINHASV 220

                         250       260       270
                  ....*....|....*....|....*....|....*.
gi 768031887  859 TFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 894
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 768031887  627 ALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRDYPSKI-----------------------LIQLCAALLLLNLVFLLDS 683
Cdd:cd15257     3 TLDIISTIGCVLSIAGLVITIIFHLHTRKLRKSSVTWVllnlcsslllfniiftsgventnNDYEISTVPDRETNTVLLS 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  684 WIALYKMQGLCISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTIS---PDN 760
Cdd:cd15257    83 EEYVEPDTDVCTAVAALLHYFLLVTFMWNAVYSAQLYLLLIRMMKPLPEMFILQASAIGWGIPAVVVAITLGATyrfPTS 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  761 YGLGSYGKfpngSPDDFCWIN--------NNAVFY--ITVVGyfcVIFLLNVSMFIVVLVQLCriKKKKQLGAQRKTSIQ 830
Cdd:cd15257   163 LPVFTRTY----RQEEFCWLAaldknfdiKKPLLWgfLLPVG---LILITNVILFIMTSQKVL--KKNNKKLTTKKRSYM 233

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768031887  831 DLRSIA-GLTFLLGITWGFAFFAW---GPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRK 888
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 768031887  694 CISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNT-YIRKYILKFCivGWGVPAVVVTIILTISPDNYGlgsygkfpng 772
Cdd:cd16007    67 CPIFAGLLHFFFLAAFSWLCLEGVQLYLMLVEVFESeYSRKKYYYLC--GYCFPALVVGISAAIDYRSYG---------- 134

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  773 sPDDFCWINNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQD--LRSIAgLTFLLGITWGFAF 850
Cdd:cd16007   135 -TEKACWLRVDNYFIWSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSwaLGAIT-LLFLLGLTWAFGL 212

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 768031887  851 FAWGPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 894
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 768031887  626 MALTFITYIGCGLSSIFLSVTLVTYIAFEKIRRD----YPSKILIQLCAALLLLNLVFLLDSWIAlykmqglCISVAVFL 701
Cdd:cd16005     2 LLLDVITWVGILLSLVCLLICIFTFCFFRGLQSDrntiHKNLCISLFVAELLFLIGINRTDQPIA-------CAVFAALL 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  702 HYFLLVSFTWMGLEAFHMYLALVKVFNT--YIRKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpngsPDDFCW 779
Cdd:cd16005    75 HFFFLAAFTWMFLEGVQLYIMLVEVFESehSRRKY---FYLVGYGMPALIVAVSAAVDYRSYG-----------TDKVCW 140

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  780 INNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKK--KKQLGAQRKTSIQDLRSIAgLTFLLGITWGFAFFAWGPVN 857
Cdd:cd16005   141 LRLDTYFIWSFIGPATLIIMLNVIFLGIALYKMFHHTAilKPESGCLDNIKSWVIGAIA-LLCLLGLTWAFGLMYINEST 219

                         250       260       270
                  ....*....|....*....|....*....|....*..
gi 768031887  858 VTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYL 894
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 768031887  694 CISVAVFLHYFLLVSFTWMGLEAFHMYLALVKVFNTYI--RKYilkFCIVGWGVPAVVVTIILTISPDNYGlgsygkfpn 771
Cdd:cd15436    67 CPIFAGLLHFFFLAAFCWLCLEGVQLYLLLVEVFESEYsrRKY---FYLCGYSFPALVVAVSAAIDYRSYG--------- 134

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768031887  772 gsPDDFCWINNNAVFYITVVGYFCVIFLLNVsmfIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIA----GLTFLLGITWG 847
Cdd:cd15436   135 --TEKACWLRVDNYFIWSFIGPVTFVITLNL---VFLVITLHKMVSHSDLLKPDSSRLDNIKSWAlgaiALLFLLGLTWS 209