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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1246417653  575 ERPICVSWNTDveDGRWTPSGCEIVEASETHTVCSCNRMANLAIIMASGE 624
Cdd:smart00303   1 FNPICVFWDES--SGEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPP 48

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 1246417653 206 DVDECSRNStLCGPTFICINTLGSYSCSCPAGFSLPT 242
Cdd:cd00054     1 DIDECASGN-PCQNGGTCVNTVGSYRCSCPPGYTGRN 36

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|..
gi 1246417653  256 DIDEC--DDTCPLNSSCTNTIGSYFCTCHPGF 285
Cdd:smart00179   1 DIDECasGNPCQNGGTCVNTVGSYRCECPPGY 32

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 1246417653  33 VNECQDTTTCPAYATCTDTTDSYYCTCKRGF 63
Cdd:cd00054     2 IDECASGNPCQNGGTCVNTVGSYRCSCPPGY 32

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 1246417653 629 FSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQT--------ACAIIAGF 700
Cdd:pfam00002   2 LSLKVIYTVGYSLSLVALLLAIAIFLLFRKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKQdldhcswvGCKVVAVF 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 701 LHYLFLACFFWMLVEAVMLFLMVrnlkvVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFI 780
Cdd:pfam00002  82 LHYFFLANFFWMLVEGLYLYTLL-----VEVFFSERKYFWWYLLIGWGVPALVVGIWAGVDPKGYGEDDGCWLSNENGLW 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 781 WSFLGPVCMIITINSVLLAWTLWVLRQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGP---LASIMAYL 857
Cdd:pfam00002 157 WIIRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDLKQYRRLAKSTLLLLPLLGITWVFGLFAFNPentLRVVFLYL 236

                         250
                  ....*....|..
gi 1246417653 858 FTIINSLQGAFI 869
Cdd:pfam00002 237 FLILNSFQGFFV 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 1246417653 577 PICVSWN-TDVEDGRWTPSGCEIVEASETHTVCSCNRMANLAII 619
Cdd:pfam01825   1 PQCVFWDfTNSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 1246417653 206 DVDECSRNStLCGPTFICINTLGSYSCSCPAGFSLPT 242
Cdd:cd00054     1 DIDECASGN-PCQNGGTCVNTVGSYRCSCPPGYTGRN 36

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1246417653  206 DVDECSRNStLCGPTFICINTLGSYSCSCPAGFS 239
Cdd:smart00179   1 DIDECASGN-PCQNGGTCVNTVGSYRCECPPGYT 33

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 1246417653 157 DEDECVTRDVCPEHATCHNTLGSYYCTCNSG 187
Cdd:cd00054     1 DIDECASGNPCQNGGTCVNTVGSYRCSCPPG 31

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1246417653 256 DIDECDDT--CPLNSSCTNTIGSYFCTCHPGF 285
Cdd:cd00054     1 DIDECASGnpCQNGGTCVNTVGSYRCSCPPGY 32

Calcium-binding EGF domain;

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1246417653 256 DIDECDD---TCPLNSSCTNTIGSYFCTCHPG 284
Cdd:pfam07645   1 DVDECATgthNCPANTVCVNTIGSFECRCPDG 32

Calcium-binding EGF domain;

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1246417653 117 DVDECLTIG-ICPKYSNCSNSVGSYSCTCQPG 147
Cdd:pfam07645   1 DVDECATGThNCPANTVCVNTIGSFECRCPDG 32

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 1246417653  33 VNECQDTTTCPAYATCTDTTDSYYCTCKRGF 63
Cdd:cd00054     2 IDECASGNPCQNGGTCVNTVGSYRCSCPPGY 32

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                          10        20        30
                  ....*....|....*....|....*....|....
gi 1246417653 303 DIDECTQDPLqCGLNSVCTNVPGSYICGCLPDFQ 336
Cdd:cd00054     1 DIDECASGNP-CQNGGTCVNTVGSYRCSCPPGYT 33

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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLA 707
Cdd:cd15931     1 DPFLEWINRVGVIVSLFCLGLAIFTFLLCRWIPKINTTAHLHLCLCLSMSHTLFLAGIEYVENELACTVMAGLLHYLFLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 708 CFFWMLVEAVMLFLMVRNLKVVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPV 787
Cdd:cd15931    81 SFVWMLLEALQLHLLVRRLTKVQVIQRDGLPRPLLCLIGYGVPFLIVGVSALVYSDGYGEAKMCWLSQERGFNWSFLGPV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 788 CMIITINSVLLAWTLWVLRQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQGA 867
Cdd:cd15931   161 IAIIGINWILFCATLWCLRQTLSNMNSDISQLKDTRLLTFKAVAQLFILGCTWVLGLFQTNPVALVFQYLFTILNSLQGA 240

                         250       260
                  ....*....|....*....|..
gi 1246417653 868 FIFLIHCLLNRQVRDEYKKLLT 889
Cdd:cd15931   241 FLFLVHCLLNKEVREEYIKWLT 262

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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLA 707
Cdd:cd15440     1 QSALTFITYIGCIISIVCLLLAFITFTCFRNLQCDRNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 708 CFFWMLVEAVMLFLMvrnlkVVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPV 787
Cdd:cd15440    81 AFSWMLLEGFQLYVM-----LVEVFEPEKSRIKWYYLFGYGLPALIVAVSAGVDPTGYGTEDHCWLSTENGFIWSFVGPV 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 788 CMIITINSVLLAWTLWVL--RQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQ 865
Cdd:cd15440   156 IVVLLANLVFLGMAIYVMcrHSSRSASKKDASKLKNIRGWLKGSIVLVVLLGLTWTFGLLFINQESIVMAYIFTILNSLQ 235

                         250       260
                  ....*....|....*....|...
gi 1246417653 866 GAFIFLIHCLLNRQVRDEYKKLL 888
Cdd:cd15440   236 GLFIFIFHCVLNEKVRKELRRWL 258

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 1246417653 631 LYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLACFF 710
Cdd:cd15252     4 LTRITQVGIIISLVCLAICIFTFWFFRGLQSDRTTIHKNLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFA 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 711 WMLVEAVMLFLMVrnlkvVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPVCMI 790
Cdd:cd15252    84 WMFIEGIQLYLML-----VEVFENEGSRHKNFYIFGYGSPAVIVGVSAALGYRYYGTTKVCWLSTENYFIWSFIGPATLI 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 791 ITINSVLLAWTLWVLRQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQGAFIF 870
Cdd:cd15252   159 ILLNLIFLGVAIYKMFRHTAGLKPEVSCLENIRSWARGAIALLFLLGLTWIFGVLHINHASVVMAYLFTVSNSLQGMFIF 238

                         250
                  ....*....|....*...
gi 1246417653 871 LIHCLLNRQVRDEYKKLL 888
Cdd:cd15252   239 LFHCVLSRKVRKEYYKLF 256

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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLA 707
Cdd:cd16007     1 ELLLSVITWVGIVISLVCLAICISTFCFLRGLQTDRNTIHKNLCINLFLAELLFLIGIDKTQYQIACPIFAGLLHFFFLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 708 CFFWMLVEAVMLFLMVrnLKVVNYFSSRNiKMLHLCafGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPV 787
Cdd:cd16007    81 AFSWLCLEGVQLYLML--VEVFESEYSRK-KYYYLC--GYCFPALVVGISAAIDYRSYGTEKACWLRVDNYFIWSFIGPV 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 788 CMIITINSVLLAWTLWVLRQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQGA 867
Cdd:cd16007   156 SFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSWALGAITLLFLLGLTWAFGLLFINKESVVMAYLFTTFNAFQGM 235

                         250       260
                  ....*....|....*....|.
gi 1246417653 868 FIFLIHCLLNRQVRDEYKKLL 888
Cdd:cd16007   236 FIFIFHCALQKKVHKEYSKCL 256

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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQ--TACAIIAGFLHYLF 705
Cdd:cd13952     1 DLALSIITYIGCSLSLVGLLLTIITYLLFPKLRNLRGKILINLCLSLLLAQLLFLIGQLLTSSDrpVLCKALAILLHYFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 706 LACFFWMLVEAVMLFLMVrnlkVVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMH-----NRCWLNTETGFI 780
Cdd:cd13952    81 LASFFWMLVEAFDLYRTF----VKVFGSSERRRFLKYSLYGWGLPLLIVIITAIVDFSLYGPSpgyggEYCWLSNGNALL 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 781 WSFLGPVCMIITINSVLLAWTLWVLRQKLcSVSSEVSKLKDTRlLTFKA-IAQIFILGCSWVLGIFQI-GPLASIMAYLF 858
Cdd:cd13952   157 WAFYGPVLLILLVNLVFFILTVRILLRKL-RETPKQSERKSDR-KQLRAyLKLFPLMGLTWIFGILAPfVGGSLVFWYLF 234

                         250       260
                  ....*....|....*....|....*.
gi 1246417653 859 TIINSLQGAFIFLIHCLLNRQVRDEY 884
Cdd:cd13952   235 DILNSLQGFFIFLIFCLKNKEVRRLL 260

Latrophilin-2, 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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLA 707
Cdd:cd16006     1 ELLLTVITWVGIVISLVCLAICIFTFCFFRGLQSDRNTIHKNLCINLFIAEFIFLIGIDKTEYKIACPIFAGLLHFFFLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 708 CFFWMLVEAVMLFLMVrnlkvVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPV 787
Cdd:cd16006    81 AFAWMCLEGVQLYLML-----VEVFESEYSRKKYYYVAGYLFPATVVGVSAAIDYKSYGTEKACWLRVDNYFIWSFIGPV 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 788 CMIITINSVLLAWTLWVLRQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQGA 867
Cdd:cd16006   156 TFIILLNLIFLVITLCKMVKHSNTLKPDSSRLENIKSWVLGAFALLCLLGLTWSFGLLFINEETIVMAYLFTIFNAFQGM 235

                         250
                  ....*....|....*....
gi 1246417653 868 FIFLIHCLLNRQVRDEYKK 886
Cdd:cd16006   236 FIFIFHCALQKKVRKEYSK 254

cadherin EGF LAG seven-pass G-type receptors, group IV adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; The group IV adhesion GPCRs include the cadherin EGF LAG seven-pass G-type receptors (CELSRs) and their Drosophila homolog Flamingo (also known as Starry night). These receptors are also classified as that belongs to the EGF-TM7 group of subfamily B2 adhesion GPCRs, because they contain EGF-like domains. Functionally, the group IV receptors act as key regulators of many physiological processes such as endocrine cell differentiation, neuronal migration, dendrite growth, axon, guidance, lymphatic vessel and valve formation, and planar cell polarity (PCP) during embryonic development. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. In the case of CELSR/Flamingo/Starry night, their extracellular domains comprise nine cadherin repeats linked to a series of epidermal growth factor (EGF)-like and laminin globular (G)-like domains. The cadherin repeats contain sequence motifs that mediate calcium-dependent cell-cell adhesion by homophilic interactions. Moreover, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. Three mammalian orthologs of Flamingo, Celsr1-3, are widely expressed in the nervous system from embryonic development until the adult stage. Each Celsr exhibits different expression patterns in the developing brain, suggesting that they serve distinct functions. Mutations of CELSR1 cause neural tube defects in the nervous system, while mutations of CELSR2 are associated with coronary heart disease. Moreover, CELSR1 and several other PCP signaling molecules, such as dishevelled, prickle, frizzled, have been shown to be upregulated in B lymphocytes of chronic lymphocytic leukemia patients. Celsr3 is expressed in both the developing and adult mouse brain. It has been functionally implicated in proper neuron migration and axon guidance in the CNS.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 629 FSLYIISHVGTVISLVCLALAIATFLLCRAVQNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYLFLAC 708
Cdd:cd15441     2 LLLKIVTYIGIGISLVLLVIAFLVLSCLRGLQSNSNSIHKNLVACLLLAELLFLLGINQTENLFPCKLIAILLHYFYLSA 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 709 FFWMLVEAVMLFLMVRNLKVVNYFssrniKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFLGPVC 788
Cdd:cd15441    82 FSWLLVESLHLYRMLTEPRDINHG-----HMRFYYLLGYGIPAIIVGLSVGLRPDGYGNPDFCWLSVNETLIWSFAGPIA 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 789 MIITINSVLLAWTLwvlrQKLCSVSSEVSKLKDTRLLTFKAIAQIFILGCSWVLGIFQIGPLASIMAYLFTIINSLQGAF 868
Cdd:cd15441   157 FVIVITLIIFILAL----RASCTLKRHVLEKASVRTDLRSSFLLLPLLGATWVFGLLAVNEDSELLHYLFAGLNFLQGLF 232

                         250       260
                  ....*....|....*....|..
gi 1246417653 869 IFLIHCLLNRQVRDEYKKLLTR 890
Cdd:cd15441   233 IFLFYCIFNKKVRRELKNALLR 254

orphan adhesion receptor GPR133, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR133 is an orphan receptor that belongs to the group V adhesion-GPCRs together with GPR144. The function of GPR144 has not yet been characterized, whereas GPR133 is highly expressed in the pituitary gland and is coupled to the Gs protein, leading to activation of adenylyl 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 1246417653 628 EFSLYIISHVGTVISLVCLALAIATFLLCRAV---QNHNTYMHLHLCVCLFLAKILFLTGIDKTDNQTACAIIAGFLHYL 704
Cdd:cd15256     1 QVALSSITYVGCSLSIFCLAITLVTFAVLSSVstiRNQRYHIHANLSFAVLVAQILLLISFRFEPGTLPCKIMAILLHFF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 705 FLACFFWMLVEAVMLFLMVrnlkvVNYFSSRNIKMLHLCAFGYGLPVLVVIISASVQPRGYGMHNRCWLNTETGFIWSFL 784
Cdd:cd15256    81 FLSAFAWMLVEGLHLYSMV-----IKVFGSEESKHFYYYGIGWGSPLLICIISLTSALDSYGESDNCWLSLENGAIWAFV 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1246417653 785 GPVCMIITIN-SVLLAWTLWVLRqkLCSVSSEVSKLKDTRLLTFKAIAQIF-ILGCSWVLGIFQIGPLASIMAYLFTIIN 862
Cdd:cd15256   156 APALFVIVVNiGILIAVTRVISR--ISADNYKVHGDANAFKLTAKAVAVLLpILGSSWVFGVLAVNTHALVFQYMFAIFN 233

                         250       260
                  ....*....|....*....|...
gi 1246417653 863 SLQGAFIFLIHCLLNRQVRDEYK 885
Cdd:cd15256   234 SLQGFFIFLFHCLLNSEVRAAFK 256