Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 2024417028   93 RSLERLDLKNNLISTIEPGAFHGLSELKRLDLSNNRIGCLTPEMFVGLNSLHKLNLSGN 151
Cdd:pfam13855    1 PNLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGN 59

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 2024417028  687 PIAAFWDFDLlDGHGGWWGEGCHIISSAGNITTIQSTHFSNFAVL 731
Cdd:pfam01825    1 PQCVFWDFTN-STTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 2024417028   93 RSLERLDLKNNLISTIEPGAFHGLSELKRLDLSNNRIGCLTPEMFVGLNSLHKLNLSGN 151
Cdd:pfam13855    1 PNLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGN 59

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 2024417028  757 AVMLLCLFASIITYIVHHStIRISRKGWHMllNFCFHTALTFAVFAGGINRIKY--------PIICQAVGIVLHYSTLST 828
Cdd:pfam00002   13 SLSLVALLLAIAIFLLFRK-LHCTRNYIHL--NLFASFILRALLFLVGDAVLFNkqdldhcsWVGCKVVAVFLHYFFLAN 89

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  829 MLWIGVTARNIYKQVTKKTQScqngdqpsyPKQPLLRFYLISGGVPFIICGITAATNINNYgieGNAPYCWMAWE-PSLG 907
Cdd:pfam00002   90 FFWMLVEGLYLYTLLVEVFFS---------ERKYFWWYLLIGWGVPALVVGIWAGVDPKGY---GEDDGCWLSNEnGLWW 157

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  908 AFYGPIAFIVLVTCIYFLCTYIQLKRHPERKYELKERTEDPQRMpstevghshitdaasipqaacsmisssllenehsfk 987
Cdd:pfam00002  158 IIRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDLKQYRRL------------------------------------ 201

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|....*...
gi 2024417028  988 aqLRAAAFTLFLFTATWTFGALAVSQG-------HFLDMIFSCLYGAF 1028
Cdd:pfam00002  202 --AKSTLLLLPLLGITWVFGLFAFNPEntlrvvfLYLFLILNSFQGFF 247

protein phosphatase 1 regulatory subunit 42; Protein phosphatase 1 regulatory subunit 42 (PPP1R42), also known as leucine-rich repeat-containing protein 67 (lrrc67) or testis leucine-rich repeat (TLRR) protein, plays a role in centrosome separation. PPP1R42 has been shown to interact with the well-conserved signaling protein phosphatase-1 (PP1) and thereby increasing PP1's activity, which counters centrosome separation. Inhibition of PPP1R42 expression increases the number of centrosomes per cell while its depletion reduces the activity of PP1 leading to activation of NEK2, the kinase responsible for phosphorylation of centrosomal linker proteins promoting centrosome separation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028   67 LPNRTvSLILSNNKILWLKNgsFFGLRSLERLDLKNNLISTIE---------------------------PGAFHGLSE- 118
Cdd:cd21340     45 LTNLT-HLYLQNNQIEKIEN--LENLVNLKKLYLGGNRISVVEglenltnleelhienqrlppgekltfdPRSLAALSNs 121

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2024417028  119 LKRLDLSNNRIGCLTPemFVGLNSLHKLNLSGNIFSSL--MNGLFSELLALKALHFN 173
Cdd:cd21340    122 LRVLNISGNNIDSLEP--LAPLRNLEQLDASNNQISDLeeLLDLLSSWPSLRELDLT 176

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 2024417028  687 PIAAFWDFDLlDGHGGWWGEGCHIISSAGNITTIQSTHFSNFAVL 731
Cdd:pfam01825    1 PQCVFWDFTN-STTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

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

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|....*..
gi 2024417028   687 PIAAFWDFDLldghGGWWGEGCHIISSAGNITTIQSTHFSNFAVLMD 733
Cdd:smart00303    3 PICVFWDESS----GEWSTRGCELLETNGTHTTCSCNHLTTFAVLMD 45

Leucine-rich repeats, outliers;

                            10        20
                    ....*....|....*....|....
gi 2024417028    92 LRSLERLDLKNNLISTIEPGAFHG 115
Cdd:smart00370    1 LPNLRELDLSNNQLSSLPPGAFQG 24

Leucine rich repeat C-terminal domain;

                            10        20        30
                    ....*....|....*....|....*....|....*.
gi 2024417028   177 LICDCNLKWVLQWARNASVR-IAEETVCAYPSALQG 211
Cdd:smart00082    3 FICDCELRWLLRWLQANEHLqDPVDLRCASPSSLRG 38

Hormone receptor domain; This extracellular domain contains four conserved cysteines that probably for disulphide bridges. The domain is found in a variety of hormone receptors. It may be a ligand binding domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2024417028  352 WPKTLAGITAYHPCLQYsfnsiaFHNGVEESKAWRKCNRTGRWDE---ENYSEC 402
Cdd:pfam02793   14 WPRTPAGETVEVPCPDY------FSGFDPRGNASRNCTEDGTWSEhppSNYSNC 61

G protein-coupled receptor 125, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR125 is an orphan receptor that has been classified as that belongs to the group III of adhesion GPCRs, which also includes orphan receptors GPR123 and GPR124. GPR125 directly interacts with dishevelled (Dvl) via its intracellular C-terminus, and together, GPR125 and Dvl recruit a subset of planar cell polarity (PCP) components into membrane subdomains, a prerequisite for activation of Wnt/PCP signaling. Thus, GPR125 influences the noncanonical WNT/PCP pathway, which does not involve beta-catenin, through interacting with and modulating the distribution of Dvl. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  746 EFLHPVVYACTAVMLLCLFASIITYIVHHSTIRISRKGWHMLLNFCFHTALTFAVFAGGINRIKYPIICQAVGIVLHYST 825
Cdd:cd15999      2 DLLHPVVYATAVVLLLCLLTIIVSYIYHHSLVRISRKSWHMLVNLCFHIFLTCAVFVGGINQTRNASVCQAVGIILHYST 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  826 LSTMLWIGVTARNIYKQVTKKTQSCQNGDQPSYPKQPLLRFYLISGGVPFIICGITAATNINNYGIEGNAPYCWMAWEPS 905
Cdd:cd15999     82 LATVLWVGVTARNIYKQVTRKAKRCQDPDEPPPPPRPMLRFYLIGGGIPIIVCGITAAANIKNYGSRPNAPYCWMAWEPS 161

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  906 LGAFYGPIAFIVLVTCIYFLCTYIQLKRHPERKYELKERTEDPQRMPSTEVGHSHITDAASiPQAACSMISSSLLENEHS 985
Cdd:cd15999    162 LGAFYGPAGFIIFVNCMYFLSIFIQLKRHPERKYELKEPTEEQQRLAASEHGELNHQDSGS-SSASCSLVSTSALENEHS 240

                          250       260       270       280       290       300       310
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2024417028  986 FKAQLRAAAFTLFLFTATWTFGALAVSQGHFLDMIFSCLYGAFCVTLGLFILIHHCAKRDDVWHCWW-SCCP 1056
Cdd:cd15999    241 FQAQLLGASLALFLYVALWIFGALAVSLYYPMDLVFSCLFGATCLSLGAFLVVHHCVNREDVRRAWIaTCCP 312

G protein-coupled receptor 124, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR124 is an orphan receptor that has been classified as that belongs to the group III of adhesion GPCRs, which also includes orphan GPR123 and GPR125. GPR124, also known as tumor endothelial marker 5 (TEM5), is highly expressed in tumor vessels and in the vasculature of the developing embryo. GPR124 is essentially required for proper angiogenic sprouting into neural tissue, CNS-specific vascularization, and formation of the blood-brain barrier. GPR124 interacts with the PDZ domain of DLG1 (discs large homolog 1) through its PDZ-binding motif. Recently, studies of double-knockout mice showed that GPR124 functions as a co-activator of Wnt7a/Wnt7b-dependent beta-catenin signaling in brain endothelium. Moreover, WNT7-stimulated beta-catenin signaling is regulated by GPR124's intracellular PDZ binding motif and leucine-rich repeats (LRR) in its N-terminal extracellular domain. The adhesion receptors are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. Furthermore, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR- autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  745 GEFLHPVVYACTAVMLLCLFASIITYIVHHSTIRISRKGWHMLLNFCFHTALTFAVFAGGINRIKYPIICQAVGIVLHYS 824
Cdd:cd15998      1 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHIAMTSAVFAGGITLTNYQMVCQAVGITLHYS 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  825 TLSTMLWIGVTARNIYKQVTKKTQSCQNGDQPSYPKQPLLRFYLISGGVPFIICGITAATNINNYgiEGNAPYCWMAWEP 904
Cdd:cd15998     81 SLSTLLWMGVKARVLHKELTWRAPPPQEGDPALPTPRPMLRFYLIAGGIPLIICGITAAVNIHNY--RDHSPYCWLVWRP 158

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  905 SLGAFYGPIAFIVLVTCIYFLCTYIQLKrhperkyelkertedpqrmpstevghSHITDAASIpqaacsmissslleneH 984
Cdd:cd15998    159 SLGAFYIPVALILLVTWIYFLCAGLHLR--------------------------GPSADGDSV----------------Y 196

                          250       260       270       280       290       300       310
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2024417028  985 SFKAQLRAAAFTLFLFTATWTFGALAVSQGHFLDMIFSCLYGAFCVTLGLFILIHHCAKRDDVWHCWWSCCP 1056
Cdd:cd15998    197 SPGVQLGALVTTHFLYLAMWACGALAVSQRWLPRVVCSCLYGVAASALGLFVFTHHCARRRDVRASWRACCP 268

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 2024417028  748 LHPVVYACTAVMLLCLFASIITYIVHHSTIRISRKgwhMLLNFCFHTALTFAVFAGGINRI--KYPIICQAVGIVLHYST 825
Cdd:cd13952      4 LSIITYIGCSLSLVGLLLTIITYLLFPKLRNLRGK---ILINLCLSLLLAQLLFLIGQLLTssDRPVLCKALAILLHYFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  826 LSTMLWIGVTARNIYKQVTKKtqscqngdQPSYPKQPLLRFYLISGGVPFIICGITAATNINNYG--IEGNAPYCWM-AW 902
Cdd:cd13952     81 LASFFWMLVEAFDLYRTFVKV--------FGSSERRRFLKYSLYGWGLPLLIVIITAIVDFSLYGpsPGYGGEYCWLsNG 152

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  903 EPSLGAFYGPIAFIVLVTCIYFLCTYIQLKRHPERKYELKERtedpqrmpstevghshitdaasipqaacsmisssllen 982
Cdd:cd13952    153 NALLWAFYGPVLLILLVNLVFFILTVRILLRKLRETPKQSER-------------------------------------- 194

                          250       260       270       280       290       300
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024417028  983 eHSFKAQLRAAAFTLFLFTATWTFGALAVSQGhfLDMIFSCLYGAFCVTLGLFILIHHCAKRDDVWHCW 1051
Cdd:cd13952    195 -KSDRKQLRAYLKLFPLMGLTWIFGILAPFVG--GSLVFWYLFDILNSLQGFFIFLIFCLKNKEVRRLL 260

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 2024417028  748 LHPVVYACTAVMLLCLfasIITYIVHhSTIRISRKGWHMLLNFCFhTALTFA--VFAGGINRIKYPIICQAVGIVLHYST 825
Cdd:cd15991      4 LKIITYTTVSLSLVAL---LITFILL-VLIRTLRSNLHSIHKNLV-AALFFSelIFLIGINQTENPFVCTVVAILLHYFY 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  826 LSTMLWIGVTARNIYKQVTKktqsCQNGDQPSypkqplLRFYLISG-GVPFIICGITAATNINNYgieGNAPYCWMAWEP 904
Cdd:cd15991     79 MSTFAWMFVEGLHIYRMLTE----VRNINTGH------MRFYYVVGwGIPAIITGLAVGLDPQGY---GNPDFCWLSVQD 145

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  905 SL-GAFYGPIAFIVLVTCIYFLctyIQLKRHPERKYELKERTedpqrmpstevghshitdaasipqAACSMisssllene 983
Cdd:cd15991    146 TLiWSFAGPIGIVVIINTVIFV---LAAKASCGRRQRYFEKS------------------------GVISM--------- 189

                          250       260       270       280       290       300
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2024417028  984 hsfkaqLRAAAFTLFLFTATWTFGALAVSQG----HFLDMIFSCLYgafcvtlGLFILIHHCAKRDDV 1047
Cdd:cd15991    190 ------LRTAFLLLLLISATWLLGLMAVNSDtlsfHYLFAIFSCLQ-------GIFIFFFHCIFNKEV 244

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 2024417028  753 YACTAVMLLCLFASIITYIVHHStIRISRKGWHMllNFCFHTALTFAVFAGGINRIKYPIICQAVGIVLHYSTLSTMLWI 832
Cdd:cd15440      9 YIGCIISIVCLLLAFITFTCFRN-LQCDRNTIHK--NLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLAAFSWM 85

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  833 GVTARNIYKQVTKKTqscqngdQPSYPKQPLlrFYLISGGVPFIICGITAATNINNYGIEgnaPYCWMAWE-PSLGAFYG 911
Cdd:cd15440     86 LLEGFQLYVMLVEVF-------EPEKSRIKW--YYLFGYGLPALIVAVSAGVDPTGYGTE---DHCWLSTEnGFIWSFVG 153

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  912 PIAFIVLVTCIYFLCTYIQLKRHPERKYELKERtedpqrmpstevghshitdaasipqaacsmissSLLENehsFKAQLR 991
Cdd:cd15440    154 PVIVVLLANLVFLGMAIYVMCRHSSRSASKKDA---------------------------------SKLKN---IRGWLK 197

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 2024417028  992 AAAFTLFLFTATWTFGALAVSQGH-FLDMIFSCLYgafcvTL-GLFILIHHCAKRDDV 1047
Cdd:cd15440    198 GSIVLVVLLGLTWTFGLLFINQESiVMAYIFTILN-----SLqGLFIFIFHCVLNEKV 250

Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2024417028   73 SLILSNNKILWLKNGSFFGLRSLERLDLKNNLISTIEPGAFHGLSELKRLDLSNNRI 129
Cdd:pfam13855    5 SLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGNRL 61

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 2024417028  757 AVMLLCLFASIITYIVHHStIRISRKGWHMLLNFCFHTALTfaVFAGGINRIKYPIICQAVGIVLHYSTLSTMLWIGVTA 836
Cdd:cd15438     13 SVSLFCLFLCILTFLFCRS-IRGTRNTIHLHLCLSLFLAHL--IFLLGINNTNNQVACAVVAGLLHYFFLAAFCWMSLEG 89

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  837 RNIYKQVTKKTQScqngdqpsypkQPLLRFYLISG--GVPFIICGITAATNINNYgieGNAPYCWMAWEPS-LGAFYGPI 913
Cdd:cd15438     90 VELYLMVVQVFNT-----------QSLKKRYLLLIgyGVPLVIVAISAAVNSKGY---GTQRHCWLSLERGfLWSFLGPV 155

                          170
                   ....*....|....*...
gi 2024417028  914 AFIVLVTCIYFLCTYIQL 931
Cdd:cd15438    156 CLIILVNAIIFVITVWKL 173

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 2024417028  746 EFLHPVVYACTAVML--LCLFASIITYIvhhSTIRISRKGWHMllNFCFHTALTFAVFAGGINRIKYPIICQAVGIVLHY 823
Cdd:cd15993      2 ETLAIVTYSSVSASLaaLVLTFSVLTCL---RGLKSNTRGIHS--NIAAALFLSELLFLLGINRTENQFLCTVVAILLHY 76

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  824 STLSTMLWIGVTARNIYKQVTkktqscqngdQPSYPKQPLLRFYLISG-GVPFIICGITAATNINNYgieGNAPYCWMA- 901
Cdd:cd15993     77 FFLSTFAWLFVQGLHIYRMQT----------EARNVNFGAMRFYYAIGwGVPAIITGLAVGLDPEGY---GNPDFCWISi 143

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  902 WEPSLGAFYGPIAFIVLVTCIYFLCtyiqlkrhperkyelkertedpqrmpstevghshitdaasIPQAACSMISSSLLE 981
Cdd:cd15993    144 HDKLVWSFAGPIVVVIVMNGVMFLL----------------------------------------VARMSCSPGQKETKK 183

                          250       260       270       280       290       300       310
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2024417028  982 NehSFKAQLRAAAFTLFLFTATWTFGALAVSQGhflDMIFSCLYGAFCVTLGLFILIHHCAKRDDVWHCWWSCC 1055
Cdd:cd15993    184 T--SVLMTLRSSFLLLLLISATWLFGLLAVNNS---VLAFHYLHAILCCLQGLAVLLLFCVLNEEVQEAWKLAC 252

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 2024417028  748 LHPVVYACTAVMLLCLFASIITYIVHHSTIRISRKGWHMllnfcfHTALTFAVFAGGI------NRIKYPIICQAVGIVL 821
Cdd:cd15256      4 LSSITYVGCSLSIFCLAITLVTFAVLSSVSTIRNQRYHI------HANLSFAVLVAQIlllisfRFEPGTLPCKIMAILL 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  822 HYSTLSTMLWIGVTARNIYKQVTKKTQScqNGDQPSYpkqpllrFYLISGGVPFIICGITAATNINNYGIEGNapyCWMA 901
Cdd:cd15256     78 HFFFLSAFAWMLVEGLHLYSMVIKVFGS--EESKHFY-------YYGIGWGSPLLICIISLTSALDSYGESDN---CWLS 145

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024417028  902 WEP-SLGAFYGPIAFIVLVTCIYFLCTYIQLKRHPERKYELKERTedpqrmpstevghshitdaasipqaacsmisssll 980
Cdd:cd15256    146 LENgAIWAFVAPALFVIVVNIGILIAVTRVISRISADNYKVHGDA----------------------------------- 190

                          250       260       270       280       290       300
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2024417028  981 eneHSFKAQLRAAAFTLFLFTATWTFGALAVSqGHFLdmIFSCLYGAFCVTLGLFILIHHCAKRDDV 1047
Cdd:cd15256    191 ---NAFKLTAKAVAVLLPILGSSWVFGVLAVN-THAL--VFQYMFAIFNSLQGFFIFLFHCLLNSEV 251

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 2024417028  757 AVMLLCLFASIITYIVHHStIRISRKGWHMllNFCFHTALTFAVFAGGINRIKYPIICQAVGIVLHYSTLSTMLWIGVTA 836
Cdd:cd16006     13 VISLVCLAICIFTFCFFRG-LQSDRNTIHK--NLCINLFIAEFIFLIGIDKTEYKIACPIFAGLLHFFFLAAFAWMCLEG 89