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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   588 LELLAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLS 667
Cdd:cd15993    1 LETLAIVTYSSVSASLAALVLTFSVLTCLRGLKSNTRGIHSNIAAALFLSELLFLLGINRTENQFLCTVVAILLHYFFLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   668 TFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIV 747
Cdd:cd15993   81 TFAWLFVQGLHIYRMQTEARNVNFGAMRFYYAIGWGVPAIITGLAVGLDPEGYGNPDFCWISIHDKLVWSFAGPIVVVIV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   748 MNGTMFLLAARTSCSTGQREAKKTSALTLRSSFLLLLLVSASW-LFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVL 826
Cdd:cd15993  161 MNGVMFLLVARMSCSPGQKETKKTSVLMTLRSSFLLLLLISATwLFGLLAVNNSVLAFHYLHAILCCLQGLAVLLLFCVL 240

                        250
                 ....*....|....
gi 3449298   827 NADARAAWMPACLG 840
Cdd:cd15993  241 NEEVQEAWKLACLG 254

Domain present in hormone receptors;

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 3449298      173 YDACPKSLRSGVWWPQTKFGVLATVPCPRGALGLRGAGAAVRLCDEAQGWLE--PDLFNCTSPAFRE 237
Cdd:smart00008    2 DLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGFSYKTGASRNCTENGGWSPpfPNYSNCTSNDYEE 68

Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in tandem arrays; the domain contains 4 disulfide bonds (loops a-d) the first three resemble epidermal growth factor (EGF); the number of copies of this domain in the different forms of laminins is highly variable ranging from 3 up to 22 copies

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 3449298   123 PCDCYPVGSTSRSCAPHSGQCPCRPGALGRQCNSCDSPF 161
Cdd:cd00055    1 PCDCNGHGSLSGQCDPGTGQCECKPNTTGRRCDRCAPGY 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
                 ....*....|....*....|....*....
gi 3449298     1 PCPPHADCRDLWQTFSCTCQPGYYGPGCV 29
Cdd:cd00054   10 PCQNGGTCVNTVGSYRCSCPPGYTGRNCE 38

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298    1171 STLPRRQPPRDYPGAMAgrfgsrdALDL----GAPREWLSTLPPPRRTRDLDPQPPPLPLSPQRQLSRDPLLpsRPLDSL 1246
Cdd:pfam03154  332 SQLQSQQPPREQPLPPA-------PLSMphikPPPTTPIPQLPNPQSHKHPPHLSGPSPFQMNSNLPPPPAL--KPLSSL 402

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298    1247 SRSsnsreqldQVPSRHPsrealgPLPQLLRAREDSVSGPSHGPSTEQLDILSSILASFNSSALSSVQSSSTPLGPHTTa 1326
Cdd:pfam03154  403 STH--------HPPSAHP------PPLQLMPQSQQLPPPPAQPPVLTQSQSLPPPAASHPPTSGLHQVPSQSPFPQHPF- 467

                          170       180       190
                   ....*....|....*....|....*....|....*.
gi 3449298    1327 TPSATASVLGPSTPRSATSHSISELSPDSEVPRSEG 1362
Cdd:pfam03154  468 VPGGPPPITPPSGPPTSTSSAMPGIQPPSSASVSSS 503

Cadherin EGF LAG seven-pass G-type receptor 3, 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. Celsr3 is expressed in both the developing and adult mouse brain. It has been functionally implicated in proper neuronal migration and axon guidance in the CNS. 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 3449298   588 LELLAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLS 667
Cdd:cd15993    1 LETLAIVTYSSVSASLAALVLTFSVLTCLRGLKSNTRGIHSNIAAALFLSELLFLLGINRTENQFLCTVVAILLHYFFLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   668 TFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIV 747
Cdd:cd15993   81 TFAWLFVQGLHIYRMQTEARNVNFGAMRFYYAIGWGVPAIITGLAVGLDPEGYGNPDFCWISIHDKLVWSFAGPIVVVIV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   748 MNGTMFLLAARTSCSTGQREAKKTSALTLRSSFLLLLLVSASW-LFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVL 826
Cdd:cd15993  161 MNGVMFLLVARMSCSPGQKETKKTSVLMTLRSSFLLLLLISATwLFGLLAVNNSVLAFHYLHAILCCLQGLAVLLLFCVL 240

                        250
                 ....*....|....
gi 3449298   827 NADARAAWMPACLG 840
Cdd:cd15993  241 NEEVQEAWKLACLG 254

GPCR-Autoproteolysis INducing (GAIN) domain; The GAIN a domain of alpha-helices and beta-strands that is found in cell-adhesion GPCRs and precedes the GPS motif where the autoproteolysis occurs, family, pfam01825. The full GAIN domain, comprises the GPS and the GAIN, in cell-adhesion GPCRs, and is the functional unit for autoproteolysis. The GPS motif at the end of the GAIN domain is an ancient domain that exists in primitive ancestor organizms, and the full GAIN + GPS is conserved in all cell-adhesion GPCRs and all PKD1-related proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298     256 EAKKLAQRLREVTGHtDHYFSQDVRVTARLLAHLlafeshqqgFGLTATQDA----HFNENLLWAGSALLAPETGDLWAA 331
Cdd:pfam16489    1 GAKELARELRNATRH-GPLYGGDVLTAVELLSQL---------FDLLATQDAtlsnAFLENFVQTVSNLLDPENRESWED 70

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298     332 LGQRAPGGSpgSAGLVRHLEEYAATLARNMEltYLNPMGLVTPNIMLSIDRMEHPSSprGARRYPRYHSNlfrgQDAWDP 411
Cdd:pfam16489   71 LQQTERGTA--ATKLLRTLEEYALLLAQNMK--YLTPFTIVTPNIVLSVDRLDTHNF--KGARFPRFPMK----GERPKD 140

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298     412 HTHVLLPsqsprpspsevlPTSSSIENSttssvvpppappepePGISIIILLVYRTLGGLLPAQ--FQAERRGARLPQNp 489
Cdd:pfam16489  141 EDSVKLP------------PKAFKPPDS---------------NGTVVVVFILYRNLGSLLPPSsrYDPDRRSLRLPRR- 192

                          250
                   ....*....|...
gi 3449298     490 VMNSPVVSVAVFH 502
Cdd:pfam16489  193 VVNSPVVSASVHS 205

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 3449298      528 SKAICVQWDPPGlaeqhGVWTARDCELVHRNGSHARCRCSRTGTFGVLMDASPR 581
Cdd:smart00303    1 FNPICVFWDESS-----GEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPPI 49

Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in tandem arrays; the domain contains 4 disulfide bonds (loops a-d) the first three resemble epidermal growth factor (EGF); the number of copies of this domain in the different forms of laminins is highly variable ranging from 3 up to 22 copies

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 3449298   123 PCDCYPVGSTSRSCAPHSGQCPCRPGALGRQCNSCDSPF 161
Cdd:cd00055    1 PCDCNGHGSLSGQCDPGTGQCECKPNTTGRRCDRCAPGY 39

Laminin EGF domain; This family is like pfam00008 but has 8 conserved cysteines instead of six.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 3449298     124 CDCYPVGSTSRSCAPHSGQCPCRPGALGRQCNSC 157
Cdd:pfam00053    1 CDCNPHGSLSDTCDPETGQCLCKPGVTGRHCDRC 34

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
                 ....*....|....*....|....*....
gi 3449298     1 PCPPHADCRDLWQTFSCTCQPGYYGPGCV 29
Cdd:cd00054   10 PCQNGGTCVNTVGSYRCSCPPGYTGRNCE 38

Laminin EGF domain; This family is like pfam00008 but has 8 conserved cysteines instead of six.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 3449298      50 PHGYTCDCVGGYFGHHCEhrmdqQCPRGWWGSPTCGPCNC 89
Cdd:pfam00053   15 PETGQCLCKPGVTGRHCD-----RCKPGYYGLPSDPPQGC 49

Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in tandem arrays; the domain contains 4 disulfide bonds (loops a-d) the first three resemble epidermal growth factor (EGF); the number of copies of this domain in the different forms of laminins is highly variable ranging from 3 up to 22 copies

                         10        20
                 ....*....|....*....|....*
gi 3449298    86 PCNCDVHKGFDPNCNKTNGQCHCKE 110
Cdd:cd00055    1 PCDCNGHGSLSGQCDPGTGQCECKP 25

EGF domain; This family includes a variety of EGF-like domain homologs. This family includes the C-terminal domain of the malaria parasite MSP1 protein.

                           10        20
                   ....*....|....*....|....*..
gi 3449298       1 PCPPHADCRDLWQTFSCTCQPGYYGPG 27
Cdd:pfam12947    7 GCHPNATCTNTGGSFTCTCNDGYTGDG 33

Laminin-type epidermal growth factor-like domai;

                            10        20
                    ....*....|....*....|....
gi 3449298       87 CNCDVHKGFDPNCNKTNGQCHCKE 110
Cdd:smart00180    1 CDCDPGGSASGTCDPDTGQCECKP 24

Cadherin EGF LAG seven-pass G-type receptor 3, 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. Celsr3 is expressed in both the developing and adult mouse brain. It has been functionally implicated in proper neuronal migration and axon guidance in the CNS. 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 3449298   588 LELLAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLS 667
Cdd:cd15993    1 LETLAIVTYSSVSASLAALVLTFSVLTCLRGLKSNTRGIHSNIAAALFLSELLFLLGINRTENQFLCTVVAILLHYFFLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   668 TFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIV 747
Cdd:cd15993   81 TFAWLFVQGLHIYRMQTEARNVNFGAMRFYYAIGWGVPAIITGLAVGLDPEGYGNPDFCWISIHDKLVWSFAGPIVVVIV 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   748 MNGTMFLLAARTSCSTGQREAKKTSALTLRSSFLLLLLVSASW-LFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVL 826
Cdd:cd15993  161 MNGVMFLLVARMSCSPGQKETKKTSVLMTLRSSFLLLLLISATwLFGLLAVNNSVLAFHYLHAILCCLQGLAVLLLFCVL 240

                        250
                 ....*....|....
gi 3449298   827 NADARAAWMPACLG 840
Cdd:cd15993  241 NEEVQEAWKLACLG 254

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 3449298   612 ILLSL-RSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVD 690
Cdd:cd15991   24 ILLVLiRTLRSNLHSIHKNLVAALFFSELIFLIGINQTENPFVCTVVAILLHYFYMSTFAWMFVEGLHIYRMLTEVRNIN 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   691 RGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAARTSCSTGQREAKK 770
Cdd:cd15991  104 TGHMRFYYVVGWGIPAIITGLAVGLDPQGYGNPDFCWLSVQDTLIWSFAGPIGIVVIINTVIFVLAAKASCGRRQRYFEK 183

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 3449298   771 TSALTLRSSFLLLLLVSASWLF-GLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADAR 831
Cdd:cd15991  184 SGVISMLRTAFLLLLLISATWLlGLMAVNSDTLSFHYLFAIFSCLQGIFIFFFHCIFNKEVR 245

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 3449298     609 TAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQ--------LVCTAVAILLHYFFLSTFAWLFVQGLHLY 680
Cdd:pfam00002   22 AIAIFLLFRKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKqdldhcswVGCKVVAVFLHYFFLANFFWMLVEGLYLY 101

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298     681 RMQVEPRNVDRGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAARTS 760
Cdd:pfam00002  102 TLLVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVDPKGYGEDDGCWLSNENGLWWIIRGPILLIILVNFIIFINIVRIL 181

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 3449298     761 CSTGQREAKKTSALTLRSSFLLLLLV-----SASWLFGLLAVNH---SILAFHYLHAGLCGLQGLAV 819
Cdd:pfam00002  182 VQKLRETNMGKSDLKQYRRLAKSTLLllpllGITWVFGLFAFNPentLRVVFLYLFLILNSFQGFFV 248

adhesion receptors, subfamily B2 of the class B family of seven-transmembrane G protein-coupled receptors; The B2 subfamily of class B GPCRs consists of cell-adhesion receptors with 33 members in humans and vertebrates. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing a variety of structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, linked to a class B seven-transmembrane domain. These include, for example, EGF (epidermal growth factor)-like domains in CD97, Celsr1 (cadherin family member), Celsr2, Celsr3, EMR1 (EGF-module-containing mucin-like hormone receptor-like 1), EMR2, EMR3, and Flamingo; two laminin A G-type repeats and nine cadherin domains in Flamingo and its human orthologs Celsr1, Celsr2 and Celsr3; olfactomedin-like domains in the latrotoxin receptors; and five or four thrombospondin type 1 repeats in BAI1 (brain-specific angiogenesis inhibitor 1), BAI2 and BAI3. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   609 TAAILLSLRSLKSNVrgIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRN 688
Cdd:cd15040   25 TYILFRKLRKRKPTK--ILLNLCLALLLANLLFLFGINSTDNPVLCTAVAALLHYFLLASFMWMLVEALLLYLRLVKVFG 102

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   689 VD-RGAMRFYHALGWGVPAVLLGLAVGLDPEGYGN-PDFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAARTSCSTGQR 766
Cdd:cd15040  103 TYpRHFILKYALIGWGLPLIIVIITLAVDPDSYGNsSGYCWLSNGNGLYYAFLGPVLLIILVNLVIFVLVLRKLLRLSAK 182

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   767 EAKKtsaltlrssFLLLLLVSASWL------------FGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARAAW 834
Cdd:cd15040  183 RNKK---------KRKKTKAQLRAAvslffllgltwiFGILAIFGARVVFQYLFAIFNSLQGFFIFIFHCLRNKEVRKAW 253

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 3449298   609 TAAILLSLRSLKsNVRG-IHANVAAALGVAELLFLLGIHRTHNQ--LVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVE 685
Cdd:cd13952   22 TIITYLLFPKLR-NLRGkILINLCLSLLLAQLLFLIGQLLTSSDrpVLCKALAILLHYFLLASFFWMLVEAFDLYRTFVK 100

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   686 PRNVDRGA-MRFYHALGWGVPAVLLGLAVGLDPEGYGNP-----DFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAART 759
Cdd:cd13952  101 VFGSSERRrFLKYSLYGWGLPLLIVIITAIVDFSLYGPSpgyggEYCWLSNGNALLWAFYGPVLLILLVNLVFFILTVRI 180

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   760 SCSTGQREAKKTSaltlrssfLLLLLVSASWLFGLLAV-------------NHSILAFHYLHAGLCGLQGLAVLLLFCVL 826
Cdd:cd13952  181 LLRKLRETPKQSE--------RKSDRKQLRAYLKLFPLmgltwifgilapfVGGSLVFWYLFDILNSLQGFFIFLIFCLK 252

                 ....*...
gi 3449298   827 NADARAAW 834
Cdd:cd13952  253 NKEVRRLL 260

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 3449298   617 RSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMRF 696
Cdd:cd15252   30 RGLQSDRTTIHKNLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFAWMFIEGIQLYLMLVEVFENEGSRHKN 109

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   697 YHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAA-----RTSCSTGQREAKKT 771
Cdd:cd15252  110 FYIFGYGSPAVIVGVSAALGYRYYGTTKVCWLSTENYFIWSFIGPATLIILLNLIFLGVAIykmfrHTAGLKPEVSCLEN 189

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   772 SALTLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADAR 831
Cdd:cd15252  190 IRSWARGAIALLFLLGLTWIFGVLHINHASVVMAYLFTVSNSLQGMFIFLFHCVLSRKVR 249

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 3449298   617 RSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMRF 696
Cdd:cd15438   30 RSIRGTRNTIHLHLCLSLFLAHLIFLLGINNTNNQVACAVVAGLLHYFFLAAFCWMSLEGVELYLMVVQVFNTQSLKKRY 109

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   697 YHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNGTMFL-----LAARTSCSTGQREAKKT 771
Cdd:cd15438  110 LLLIGYGVPLVIVAISAAVNSKGYGTQRHCWLSLERGFLWSFLGPVCLIILVNAIIFVitvwkLAEKFSSINPDMEKLRK 189

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 3449298   772 SALTLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARA 832
Cdd:cd15438  190 IRALTITAIAQLCILGCTWIFGFFQFSDSTLVMSYLFTILNSLQGLFIFLLHCLLSKQVRE 250

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 3449298   616 LRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMR 695
Cdd:cd16007   29 LRGLQTDRNTIHKNLCINLFLAELLFLIGIDKTQYQIACPIFAGLLHFFFLAAFSWLCLEGVQLYLMLVEVFESEYSRKK 108

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   696 FYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNgTMFLLAARTSCSTGQREAKKTSALT 775
Cdd:cd16007  109 YYYLCGYCFPALVVGISAAIDYRSYGTEKACWLRVDNYFIWSFIGPVSFVIVVN-LVFLMVTLHKMIRSSSVLKPDSSRL 187

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 3449298   776 LRSSFLLLLLVS------ASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVL 826
Cdd:cd16007  188 DNIKSWALGAITllfllgLTWAFGLLFINKESVVMAYLFTTFNAFQGMFIFIFHCAL 244

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 3449298   616 LRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQLVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMR 695
Cdd:cd16005   29 FRGLQSDRNTIHKNLCISLFVAELLFLIGINRTDQPIACAVFAALLHFFFLAAFTWMFLEGVQLYIMLVEVFESEHSRRK 108

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 3449298   696 FYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNgTMFLLAA------RTSCSTGQREAK 769
Cdd:cd16005  109 YFYLVGYGMPALIVAVSAAVDYRSYGTDKVCWLRLDTYFIWSFIGPATLIIMLN-VIFLGIAlykmfhHTAILKPESGCL 187

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 3449298   770 KTSALTLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARAAW 834
Cdd:cd16005  188 DNIKSWVIGAIALLCLLGLTWAFGLMYINESTVIMAYLFTIFNSLQGMFIFIFHCVLQKKVRKEY 252