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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15439    1 DLALTVITYVGLIISLLCLFLAILTFLLCRSIRNTSTSLHLQLSLCLFLADLLFLVGIDRTDNKVLCSIIAGFLHYLFLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMVRNLKVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15439   81 CFAWMFLEAVHLFLTVRNLKVVNYFSSHRFKKRFMYPVGYGLPAVIVAISAAVNPQGYGTPKHCWLSMEKGFIWSFLGPV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15439  161 CVIIV---INLVLFCLTLWILREKLSSLNAEVSTLKNTRLLTFKAIAQLFILGCTWILGLFQVGPVATVMAYLFTITNSL 237

                        250       260
                 ....*....|....*....|....*.
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKRWITG 864
Cdd:cd15439  238 QGVFIFLVHCLLNRQVREEYRRWITG 263

Calcium-binding EGF-like domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 158261825   132 DINECLTSSVCPEHSDCVNSMGSYSCSCQVGFISRNsTCE 171
Cdd:smart00179   1 DIDECASGNPCQNGGTCVNTVGSYRCECPPGYTDGR-NCE 39

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|..
gi 158261825   221 DIDECTEM--CPINSTCTNTPGSYFCTCHPGF 250
Cdd:smart00179   1 DIDECASGnpCQNGGTCVNTVGSYRCECPPGY 32

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|....
gi 158261825   268 DIDECrQDPSTCGPNSICTNALGSYSCGCIAGFH 301
Cdd:smart00179   1 DIDEC-ASGNPCQNGGTCVNTVGSYRCECPPGYT 33

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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15439    1 DLALTVITYVGLIISLLCLFLAILTFLLCRSIRNTSTSLHLQLSLCLFLADLLFLVGIDRTDNKVLCSIIAGFLHYLFLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMVRNLKVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15439   81 CFAWMFLEAVHLFLTVRNLKVVNYFSSHRFKKRFMYPVGYGLPAVIVAISAAVNPQGYGTPKHCWLSMEKGFIWSFLGPV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15439  161 CVIIV---INLVLFCLTLWILREKLSSLNAEVSTLKNTRLLTFKAIAQLFILGCTWILGLFQVGPVATVMAYLFTITNSL 237

                        250       260
                 ....*....|....*....|....*.
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKRWITG 864
Cdd:cd15439  238 QGVFIFLVHCLLNRQVREEYRRWITG 263

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 158261825   546 ERPICVSWSTDVkgGRWTSFGCVILEASETYTICSCNQMANLAVIMASGE 595
Cdd:smart00303   1 FNPICVFWDESS--GEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPP 48

Calcium-binding EGF-like domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 158261825   132 DINECLTSSVCPEHSDCVNSMGSYSCSCQVGFISRNsTCE 171
Cdd:smart00179   1 DIDECASGNPCQNGGTCVNTVGSYRCECPPGYTDGR-NCE 39

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        40
                 ....*....|....*....|....*....|....*....|
gi 158261825 132 DINECLTSSVCPEHSDCVNSMGSYSCSCQVGFISRNstCE 171
Cdd:cd00054    1 DIDECASGNPCQNGGTCVNTVGSYRCSCPPGYTGRN--CE 38

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|..
gi 158261825   221 DIDECTEM--CPINSTCTNTPGSYFCTCHPGF 250
Cdd:smart00179   1 DIDECASGnpCQNGGTCVNTVGSYRCECPPGY 32

Calcium-binding EGF domain;

                          10        20        30
                  ....*....|....*....|....*....|..
gi 158261825  172 DVDECADPRA-CPEHATCNNTVGNYSCFCNPG 202
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 158261825  80 DIDECSqSPQPCGPNSSCKNLSGRYKCSCLDGFS 113
Cdd:cd00054    1 DIDECA-SGNPCQNGGTCVNTVGSYRCSCPPGYT 33

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|....
gi 158261825   268 DIDECrQDPSTCGPNSICTNALGSYSCGCIAGFH 301
Cdd:smart00179   1 DIDEC-ASGNPCQNGGTCVNTVGSYRCECPPGYT 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 158261825 268 DIDECrQDPSTCGPNSICTNALGSYSCGCIAGFH 301
Cdd:cd00054    1 DIDEC-ASGNPCQNGGTCVNTVGSYRCSCPPGYT 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 158261825  33 NNCRDSTLCPAYATCTNTVDSYYCACKQGF 62
Cdd:cd00054    3 DECASGNPCQNGGTCVNTVGSYRCSCPPGY 32

Calcium-binding EGF-like domain;

                           10        20        30
                   ....*....|....*....|....*....|
gi 158261825    33 NNCRDSTLCPAYATCTNTVDSYYCACKQGF 62
Cdd:smart00179   3 DECASGNPCQNGGTCVNTVGSYRCECPPGY 32

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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15439    1 DLALTVITYVGLIISLLCLFLAILTFLLCRSIRNTSTSLHLQLSLCLFLADLLFLVGIDRTDNKVLCSIIAGFLHYLFLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMVRNLKVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15439   81 CFAWMFLEAVHLFLTVRNLKVVNYFSSHRFKKRFMYPVGYGLPAVIVAISAAVNPQGYGTPKHCWLSMEKGFIWSFLGPV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15439  161 CVIIV---INLVLFCLTLWILREKLSSLNAEVSTLKNTRLLTFKAIAQLFILGCTWILGLFQVGPVATVMAYLFTITNSL 237

                        250       260
                 ....*....|....*....|....*.
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKRWITG 864
Cdd:cd15439  238 QGVFIFLVHCLLNRQVREEYRRWITG 263

CD97 antigen, member of the class B2 family of seven-transmembrane G protein-coupled receptors; group II adhesion GPCRs, including the leukocyte cell-surface antigen CD97 and the epidermal growth factor (EGF)-module-containing, mucin-like hormone receptor (EMR1-4), are primarily expressed in cells of the immune system. All EGF-TM7 receptors, which belong to the B2 subfamily B2 of adhesion GPCRs, are members of group II, except for ETL (EGF-TM7-latrophilin related protein), which is classified into group I. Members of the EGF-TM7 receptors are characterized by the presence of varying numbers of N-terminal EGF-like domains, which play critical roles in ligand recognition and cell adhesion, linked by a stalk region to a class B seven-transmembrane domain. In the case of CD97, alternative splicing results in three isoforms possessing either three (EGF1,2,5), four (EGF1,2,3,5) or five (EGF1,2,3,4,5) EGF-like domains. Moreover, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions. For example, CD97, which is involved in angiogenesis and the migration and invasion of tumor cells, has been shown to promote cell aggregation in a GPS proteolysis-dependent manner. CD97 is widely expressed on lymphocytes, monocytes, macrophages, dendritic cells, granulocytes and smooth muscle cells as well as in a variety of human tumors including colorectal, gastric, esophageal pancreatic, and thyroid carcinoma. EMR2 shares strong sequence homology with CD97, differing by only six amino acids. However, unlike CD97, EMR2 is not found in those of CD97-positive tumor cells and is not expressed on lymphocytes but instead on monocytes, macrophages and granulocytes. CD97 has three known ligands: CD55, decay-accelerating factor for regulation of complement system; chondroitin sulfate, a glycosaminoglycan found in the extracellular matrix; and the integrin alpha5beta1, which play a role in angiogenesis. Although EMR2 does not effectively interact with CD55, the fourth EGF-like domain of this receptor binds to chondroitin sulfate to mediate cell attachment.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15438    1 DWPLTLITKVGLSVSLFCLFLCILTFLFCRSIRGTRNTIHLHLCLSLFLAHLIFLLGINNTNNQVACAVVAGLLHYFFLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMvrnlkVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15438   81 AFCWMSLEGVELYLM-----VVQVFNTQSLKKRYLLLIGYGVPLVIVAISAAVNSKGYGTQRHCWLSLERGFLWSFLGPV 155

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15438  156 CLIIL---VNAIIFVITVWKLAEKFSSINPDMEKLRKIRALTITAIAQLCILGCTWIFGFFQFSDSTLVMSYLFTILNSL 232

                        250       260
                 ....*....|....*....|....
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKRWI 862
Cdd:cd15438  233 QGLFIFLLHCLLSKQVREEYSRWL 256

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 158261825 600 FSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLAC 679
Cdd:cd15440    2 SALTFITYIGCIISIVCLLLAFITFTCFRNLQCDRNTIHKNLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLAA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 680 FFWMLVEAVILFLMvrnlkVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPVC 759
Cdd:cd15440   82 FSWMLLEGFQLYVM-----LVEVFEPEKSRIKWYYLFGYGLPALIVAVSAGVDPTGYGTEDHCWLSTENGFIWSFVGPVI 156

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 760 TVIVtlqINSL--LLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINS 837
Cdd:cd15440  157 VVLL---ANLVflGMAIYVMCRHSSRSASKKDASKLKNIRGWLKGSIVLVVLLGLTWTFGLLFINQESIVMAYIFTILNS 233

                        250       260
                 ....*....|....*....|....*
gi 158261825 838 LQGAFIFLIHCLLNGQVREEYKRWI 862
Cdd:cd15440  234 LQGLFIFIFHCVLNEKVRKELRRWL 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 158261825 602 LYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLACFF 681
Cdd:cd15933    4 LSIISYIGCGISIACLALTLIIFLVLRVLSSDRFQIHKNLCVALLLAQILLLAGEWAEGNKVACKVVAILLHFFFMAAFS 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 682 WMLVEAVILFLMVrnLKVVNYFSsrnikMLHIC-AFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPVCT 760
Cdd:cd15933   84 WMLVEGLHLYLMI--VKVFNYKS-----KMRYYyFIGWGLPAIIVAISLAILFDDYGSPNVCWLSLDDGLIWAFVGPVIF 156

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 761 VIVtlqINsLLLTWTLWILRQRLSSVNAEVSTLKDTRL-LTFKAFAQLF-ILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15933  157 IIT---VN-TVILILVVKITVSLSTNDAKKSQGTLAQIkSTAKASVVLLpILGLTWLFGVLVVNSQTIVFQYIFVILNSL 232

                        250       260
                 ....*....|....*....|
gi 158261825 839 QGAFIFLIHCLLNGQVREEY 858
Cdd:cd15933  233 QGLMIFLFHCVLNSEVRSAF 252

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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKM--GCAIIAGFLHYLF 676
Cdd:cd13952    1 DLALSIITYIGCSLSLVGLLLTIITYLLFPKLRNLRGKILINLCLSLLLAQLLFLIGQLLTSSDRpvLCKALAILLHYFL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 677 LACFFWMLVEAVILFLMVrnlkVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMH-----NRCWLNTETGFI 751
Cdd:cd13952   81 LASFFWMLVEAFDLYRTF----VKVFGSSERRRFLKYSLYGWGLPLLIVIITAIVDFSLYGPSpgyggEYCWLSNGNALL 156

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 752 WSFLGPVCTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRllTFKAFAQLFIL-GCSWVLGIFQIGPVAG-VMA 829
Cdd:cd13952  157 WAFYGPVLLILL---VNLVFFILTVRILLRKLRETPKQSERKSDRK--QLRAYLKLFPLmGLTWIFGILAPFVGGSlVFW 231

                        250       260
                 ....*....|....*....|....*....
gi 158261825 830 YLFTIINSLQGAFIFLIHCLLNGQVREEY 858
Cdd:cd13952  232 YLFDILNSLQGFFIFLIFCLKNKEVRRLL 260

Epidermal Growth Factor, latrophilin and seven transmembrane domain-containing protein 1; member of the class B2 family of seven-transmembrane G protein-coupled receptors; ETL (EGF-TM7-latrophilin-related protein) belongs to Group I adhesion GPCRs, which also include latrophilins (also called lectomedins or latrotoxin receptors). 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. ETL, for instance, contains EGF-like repeats, which also present in other EGF-TM7 adhesion GPCRs, such as Cadherin EGF LAG seven-pass G-type receptors (CELSR1-3), EGF-like module receptors (EMR1-3), CD97, and Flamingo. ETL is highly expressed in heart, where developmentally regulated, as well as in normal smooth cells. 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 158261825 605 ISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLACFFWML 684
Cdd:cd15437    7 ITQLGIIISLICLSMCIFTFWFFSEIQSTRTTIHKNLCCSLFLAELIFLIGINMNANKLFCSIIAGLLHYFFLAAFAWMC 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 685 VEAVILFLMVRNLKVVNYFSSRNIKmlhicAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPVCTVIVt 764
Cdd:cd15437   87 IEGIHLYLIVVGVIYNKGFLHKNFY-----IFGYGSPAVVVGISAALGYKYYGTTKVCWLSTENNFIWSFIGPACLIIL- 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 765 lqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSLQGAFIF 844
Cdd:cd15437  161 --VNLLAFGVIIYKVFRHTAMLKPEVSCYENIRSCARGALALLFLLGATWIFGVLHVVYGSVVTAYLFTISNAFQGMFIF 238

                        250
                 ....*....|....*.
gi 158261825 845 LIHCLLNGQVREEYKR 860
Cdd:cd15437  239 IFLCVLSRKIQEEYYR 254

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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15436    1 ELLLFVITWVGIVISLVCLLICIFTFCFFRGLQTDRNTIHKNLCINLFIAELLFLIGINRTQYTIACPIFAGLLHFFFLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMVRNLkvvnyFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15436   81 AFCWLCLEGVQLYLLLVEV-----FESEYSRRKYFYLCGYSFPALVVAVSAAIDYRSYGTEKACWLRVDNYFIWSFIGPV 155

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15436  156 TFVIT---LNLVFLVITLHKMVSHSDLLKPDSSRLDNIKSWALGAIALLFLLGLTWSFGLMFINEESVVMAYLFTIFNAF 232

                        250       260
                 ....*....|....*....|..
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKR 860
Cdd:cd15436  233 QGVFIFIFHCALQKKVRKEYSK 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 158261825 599 DFSLYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLA 678
Cdd:cd15441    1 VLLLKIVTYIGIGISLVLLVIAFLVLSCLRGLQSNSNSIHKNLVACLLLAELLFLLGINQTENLFPCKLIAILLHYFYLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 679 CFFWMLVEAVILFLMVRNLKVVNYFssrniKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPV 758
Cdd:cd15441   81 AFSWLLVESLHLYRMLTEPRDINHG-----HMRFYYLLGYGIPAIIVGLSVGLRPDGYGNPDFCWLSVNETLIWSFAGPI 155

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 759 CTVIVtlqINSLLLTWTLWILRqRLSSVNAEVSTLkdtRLLTFKAFAQLFILGCSWVLGIFQIGPVAGVMAYLFTIINSL 838
Cdd:cd15441  156 AFVIV---ITLIIFILALRASC-TLKRHVLEKASV---RTDLRSSFLLLPLLGATWVFGLLAVNEDSELLHYLFAGLNFL 228

                        250       260
                 ....*....|....*....|..
gi 158261825 839 QGAFIFLIHCLLNGQVREEYKR 860
Cdd:cd15441  229 QGLFIFLFYCIFNKKVRRELKN 250

Cadherin EGF LAG seven-pass G-type receptor 1, 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. 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. 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 602 LYIISHVGIIISLVCLVLAIATFLLCRSIRNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLACFF 681
Cdd:cd15991    4 LKIITYTTVSLSLVALLITFILLVLIRTLRSNLHSIHKNLVAALFFSELIFLIGINQTENPFVCTVVAILLHYFYMSTFA 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158261825 682 WMLVEAVILFLMVRNLKVVNyfsSRNIKMLHicAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIWSFLGPVCTV 761
Cdd:cd15991   84 WMFVEGLHIYRMLTEVRNIN---TGHMRFYY--VVGWGIPAIITGLAVGLDPQGYGNPDFCWLSVQDTLIWSFAGPIGIV 158