Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1039791003  130 TLLLSNNKITGLRNGSFLGLSLLEKLDLRSNVISTVQPGAFLGLGELKRLDLSNNRI 186
Cdd:pfam13855    5 SLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGNRL 61

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1039791003   393 SYCPAErvtnNRGDFRWPRTLAGITAYQSCLQYpftsvpLSGGAPGTRASRRCDRAGRWEPG--DYSHC 459
Cdd:smart00008    3 LGCPAT----WDGIICWPQTPAGQLVEVPCPKY------FSGFSYKTGASRNCTENGGWSPPfpNYSNC 61

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  299 VVFQGDRLPFQCSASYLGNDTRIHWYHNGapMESDEQAGIVLAENLIHdctfiTSELTLSHIGVWASGEWECSVSTVQGN 378
Cdd:pfam00047    7 TVLEGDSATLTCSASTGSPGPDVTWSKEG--GTLIESLKVKHDNGRTT-----QSSLLISNVTKEDAGTYTCVVNNPGGS 79

                   ....*..
gi 1039791003  379 TSKKVEI 385
Cdd:pfam00047   80 ATLSTSL 86

Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1039791003  130 TLLLSNNKITGLRNGSFLGLSLLEKLDLRSNVISTVQPGAFLGLGELKRLDLSNNRI 186
Cdd:pfam13855    5 SLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGNRL 61

Leucine-rich repeat (LRR) protein [Transcription];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  114 DLPEPPDPglLPNgTITLLLSNNKITGLRNgSFLGLSLLEKLDLRSNVISTVqPGAFLGLGELKRLDLSNNRIGCLTSet 193
Cdd:COG4886    173 DLPEELGN--LTN-LKELDLSNNQITDLPE-PLGNLTNLEELDLSGNQLTDL-PEPLANLTNLETLDLSNNQLTDLPE-- 245

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1039791003  194 FQGLPRLLRLNISGNIYSSLQPGVfdELPALKIVDFGTEFLTcDCRLRWLLPWARNHSLQLSERTL 259
Cdd:COG4886    246 LGNLTNLEELDLSNNQLTDLPPLA--NLTNLKTLDLSNNQLT-DLKLKELELLLGLNSLLLLLLLL 308

Leucine rich repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1039791003  175 ELKRLDLSNNRIGCLTSETFQGLPRLLRLNISGNIYSSLQPGVFDELPALKIVD 228
Cdd:pfam13855    2 NLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLD 55

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 1039791003  131 LLLSNNKITGLRNgsFLGLSLLEKLDLRSNVISTV---------------------------QPGAFLGLGE-LKRLDLS 182
Cdd:cd21340     51 LYLQNNQIEKIEN--LENLVNLKKLYLGGNRISVVeglenltnleelhienqrlppgekltfDPRSLAALSNsLRVLNIS 128

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1039791003  183 NNRIGCLTSetFQGLPRLLRLNISGNIYSSLQP--GVFDELPALKIVDF 229
Cdd:cd21340    129 GNNIDSLEP--LAPLRNLEQLDASNNQISDLEEllDLLSSWPSLRELDL 175

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 1039791003  751 PMAAWWNQ--DGPGGWSSEGCRLRYSQPNVSSLYCQHLGNVAVL 792
Cdd:pfam01825    1 PQCVFWDFtnSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Leucine rich repeat C-terminal domain;

                            10        20        30
                    ....*....|....*....|....*....|....*
gi 1039791003   234 LTCDCRLRWLLPWARNHS-LQLSERTLCAYPSALH 267
Cdd:smart00082    3 FICDCELRWLLRWLQANEhLQDPVDLRCASPSSLR 37

Immunoglobulin domain; Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  299 VVFQGDRLPFQCSASYLGNDTRIHWYHNGapMESDEQAGIVLAENLIHdctfiTSELTLSHIGVWASGEWECSVSTVQGN 378
Cdd:pfam00047    7 TVLEGDSATLTCSASTGSPGPDVTWSKEG--GTLIESLKVKHDNGRTT-----QSSLLISNVTKEDAGTYTCVVNNPGGS 79

                   ....*..
gi 1039791003  379 TSKKVEI 385
Cdd:pfam00047   80 ATLSTSL 86

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003 1090 PPASPSAShVPARALPTATEDGSPVLGEGPASLKSSPSGSSGRAP--PPPCKLTNLQVAQSQVCEASVAARGDGEPEPTG 1167
Cdd:PHA03307   185 APSSPPAE-PPPSTPPAAASPRPPRRSSPISASASSPAPAPGRSAadDAGASSSDSSSSESSGCGWGPENECPLPRPAPI 263

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003 1168 SRGSLAPRHHNNLHHGRRVHKSRAKGHRAGETGGKSRLKALRAGTSPGAPELLSSESGSLHNSPSDSYPGSSRNSPGDGL 1247
Cdd:PHA03307   264 TLPTRIWEASGWNGPSSRPGPASSSSSPRERSPSPSPSSPGSGPAPSSPRASSSSSSSRESSSSSTSSSSESSRGAAVSP 343

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1039791003 1248 PLEGEPMLTPSEGSDTSAAPiaetgRPGQRRSASRDNLKGSGSALERESKRRSY 1301
Cdd:PHA03307   344 GPSPSRSPSPSRPPPPADPS-----SPRKRPRPSRAPSSPAASAGRPTRRRARA 392

orphan GPR124 and related proteins, group III adhesion GPCRs, member of class B2 family of seven-transmembrane G protein-coupled receptors; group III adhesion GPCRs include orphan GPR123, GPR124, GPR125, and their closely related proteins. 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. GPR123 is predominantly expressed in the CNS including thalamus, brain stem and regions containing large pyramidal cells. 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 also 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. Furthermore, 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. 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  806 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYS 885
Cdd:cd15259      1 FELLHPVVYAGAALCLLCLLATIITYIVFHRLIRISRKGRHMLVNLCLHLLLTCVVFVGGINRTANQLVCQAVGILLHYS 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  886 SLSSLLWMGVKARVLHKELSWRAPPLEEGEAAPPGPRPMLRFYLIAGGIPLIICGITAAVNIHNYrDHSPYCWLVWRPSL 965
Cdd:cd15259     81 TLCTLLWVGVTARNMYKQVTKTAKPPQDEDQPPRPPKPMLRFYLIGWGIPLIICGITAAVNLDNY-STYDYCWLAWDPSL 159

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  966 GAFYIPVALILPITWIYFLCAGLHLRSHVAqnpkqvsagvgtpappedgdgvySPGVQLGALMTTHFLYLAMWACGALAV 1045
Cdd:cd15259    160 GAFYGPAALIVLVNCIYFLRIYCQLKGAPV-----------------------SFQSQLRGAVITLFLYVAMWACGALAV 216

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|....
gi 1039791003 1046 SQRWLPRVVCSCLYGVAASALGLFVFTHHCARRRDVRASWRACC 1089
Cdd:cd15259    217 SQRYFLDLVFSCLYGATCSSLGLFVLIHHCLSREDVRQSWRQCC 260

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 1039791003  809 LHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLS 888
Cdd:cd15999      4 LHPVVYATAVVLLLCLLTIIVSYIYHHSLVRISRKSWHMLVNLCFHIFLTCAVFVGGINQTRNASVCQAVGIILHYSTLA 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  889 SLLWMGVKARVLHKELSWRAPPLEEGEAAPPGPRPMLRFYLIAGGIPLIICGITAAVNIHNY--RDHSPYCWLVWRPSLG 966
Cdd:cd15999     84 TVLWVGVTARNIYKQVTRKAKRCQDPDEPPPPPRPMLRFYLIGGGIPIIVCGITAAANIKNYgsRPNAPYCWMAWEPSLG 163

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  967 AFYIPVALILPITWIYFLCAGLHLRSH---------VAQNPKQVSAGVGTPAPPED-GDGVYSPG-VQLGALMTTH---- 1031
Cdd:cd15999    164 AFYGPAGFIIFVNCMYFLSIFIQLKRHperkyelkePTEEQQRLAASEHGELNHQDsGSSSASCSlVSTSALENEHsfqa 243

                          250       260       270       280       290       300
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1039791003 1032 ---------FLYLAMWACGALAVSQRWLPRVVCSCLYGVAASALGLFVFTHHCARRRDVRASW-RACCP 1090
Cdd:cd15999    244 qllgaslalFLYVALWIFGALAVSLYYPMDLVFSCLFGATCLSLGAFLVVHHCVNREDVRRAWiATCCP 312

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 1039791003  809 LHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKgwhMLLNLCFHMAMTSAVFVGGVTLTNYQM--VCQAVGITLHYSS 886
Cdd:cd13952      4 LSIITYIGCSLSLVGLLLTIITYLLFPKLRNLRGK---ILINLCLSLLLAQLLFLIGQLLTSSDRpvLCKALAILLHYFL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  887 LSSLLWMGVKARVLHKELSWRAPPLEegeaappgPRPMLRFYLIAGGIPLIICGITAAVNIHNYRDHSPY----CWL-VW 961
Cdd:cd13952     81 LASFFWMLVEAFDLYRTFVKVFGSSE--------RRRFLKYSLYGWGLPLLIVIITAIVDFSLYGPSPGYggeyCWLsNG 152

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  962 RPSLGAFYIPVALILPITWIYFLCAGLHLRSHVAQNPKQVSAGvgtpappedgdgvySPGVQLGALMTTHFLYLAMWACG 1041
Cdd:cd13952    153 NALLWAFYGPVLLILLVNLVFFILTVRILLRKLRETPKQSERK--------------SDRKQLRAYLKLFPLMGLTWIFG 218

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|....
gi 1039791003 1042 ALAVSQRWlpRVVCSCLYGVAASALGLFVFTHHCARRRDVRASW 1085
Cdd:cd13952    219 ILAPFVGG--SLVFWYLFDILNSLQGFFIFLIFCLKNKEVRRLL 260

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 1039791003  812 VVYPCTALLLLCLFSTIITYIlnhsSIHVSRKGWHML-LNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLSSL 890
Cdd:cd15933      7 ISYIGCGISIACLALTLIIFL----VLRVLSSDRFQIhKNLCVALLLAQILLLAGEWAEGNKVACKVVAILLHFFFMAAF 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  891 LWMGVKARVLHKELswrappleegeAAPPGPRPMLRFYLIAG-GIPLIICGITAAVNIHNYRDHSpYCWL------VWrp 963
Cdd:cd15933     83 SWMLVEGLHLYLMI-----------VKVFNYKSKMRYYYFIGwGLPAIIVAISLAILFDDYGSPN-VCWLslddglIW-- 148

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  964 slgAFYIPVALILPITWIYFLC---AGLHLRSHVAQNPKQVSAGVGTPAPpedgdgvyspgvqlGALMTTHFLYLAmWAC 1040
Cdd:cd15933    149 ---AFVGPVIFIITVNTVILILvvkITVSLSTNDAKKSQGTLAQIKSTAK--------------ASVVLLPILGLT-WLF 210

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|....*
gi 1039791003 1041 GALAVSQRwlpRVVCSCLYGVAASALGLFVFTHHCARRRDVRASW 1085
Cdd:cd15933    211 GVLVVNSQ---TIVFQYIFVILNSLQGLMIFLFHCVLNSEVRSAF 252

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 1039791003  821 LLCLFSTIITYILNHS------SIHVsrkgwhmllNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLSSLLWMG 894
Cdd:cd15440     16 IVCLLLAFITFTCFRNlqcdrnTIHK---------NLCLCLLIAEIVFLLGIDQTENRTLCGVIAGLLHYFFLAAFSWML 86

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  895 VKARVLHKELSwrappleegEAAPPGPRPMLRFYLIAGGIPLIICGITAAVNIHNYrDHSPYCWL------VWrpslgAF 968
Cdd:cd15440     87 LEGFQLYVMLV---------EVFEPEKSRIKWYYLFGYGLPALIVAVSAGVDPTGY-GTEDHCWLstengfIW-----SF 151

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  969 YIPVALILPITWIYFLCAGLHLRSHvaqnpkqvsaGVGTPAPPEDGDGVYSPGVQLGALMTTHFLYLAmWACGALAVSQR 1048
Cdd:cd15440    152 VGPVIVVLLANLVFLGMAIYVMCRH----------SSRSASKKDASKLKNIRGWLKGSIVLVVLLGLT-WTFGLLFINQE 220

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 1039791003 1049 wlpRVVCSCLYGVAASALGLFVFTHHCARRRDVRASWRACC 1089
Cdd:cd15440    221 ---SIVMAYIFTILNSLQGLFIFIFHCVLNEKVRKELRRWL 258

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 1039791003  821 LLCLFSTIITYILNHSsIHVSRKGWHMLLNLCFHMAMTsaVFVGGVTLTNYQMVCQAVGITLHYSSLSSLLWMGVKArvL 900
Cdd:cd15439     16 LLCLFLAILTFLLCRS-IRNTSTSLHLQLSLCLFLADL--LFLVGIDRTDNKVLCSIIAGFLHYLFLACFAWMFLEA--V 90

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  901 HKELSWRAPPLEEGEAAppgPRPMLRF-YLIAGGIPLIICGITAAVNIHNYRDHSpYCWL------VWrpslgAFYIPVA 973
Cdd:cd15439     91 HLFLTVRNLKVVNYFSS---HRFKKRFmYPVGYGLPAVIVAISAAVNPQGYGTPK-HCWLsmekgfIW-----SFLGPVC 161

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  974 LILPITWIYFLCAGLHLRSHVAQNPKQVSAgvgtpappedgdgvyspgVQLGALMT----THFLYLAM-WACGALAVSQr 1048
Cdd:cd15439    162 VIIVINLVLFCLTLWILREKLSSLNAEVST------------------LKNTRLLTfkaiAQLFILGCtWILGLFQVGP- 222

                          250       260       270
                   ....*....|....*....|....*....|....*...
gi 1039791003 1049 wlPRVVCSCLYGVAASALGLFVFTHHCARRRDVRASWR 1086
Cdd:cd15439    223 --VATVMAYLFTITNSLQGVFIFLVHCLLNRQVREEYR 258

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  816 CTALLLLCLFSTIITYILNhSSIHVSRKGWHmlLNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLSSLLWMGV 895
Cdd:cd15931     11 GVIVSLFCLGLAIFTFLLC-RWIPKINTTAH--LHLCLCLSMSHTLFLAGIEYVENELACTVMAGLLHYLFLASFVWMLL 87

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  896 KARVLHkelsWRAPPLEEGEAAPPGPRPMLRFYLIAGGIPLIICGITAAVNIHNYRDHSpYCWLVW-RPSLGAFYIPVAL 974
Cdd:cd15931     88 EALQLH----LLVRRLTKVQVIQRDGLPRPLLCLIGYGVPFLIVGVSALVYSDGYGEAK-MCWLSQeRGFNWSFLGPVIA 162

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  975 ILPITWIYFLCAGLHLRSHVAQNPKQVSAGVGTPAPpedgdgVYSPGVQLgalmtthFLYLAMWACGALAVSQRWLprvV 1054
Cdd:cd15931    163 IIGINWILFCATLWCLRQTLSNMNSDISQLKDTRLL------TFKAVAQL-------FILGCTWVLGLFQTNPVAL---V 226

                          250       260       270
                   ....*....|....*....|....*....|..
gi 1039791003 1055 CSCLYGVAASALGLFVFTHHCARRRDVRASWR 1086
Cdd:cd15931    227 FQYLFTILNSLQGAFLFLVHCLLNKEVREEYI 258

Probable G protein-coupled receptor 112, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR112 is an orphan receptor that has been classified as that belongs to the Group VIII of adhesion GPCRs. Other members of the Group VII include orphan GPCRs such as GPR56, GPR64, GPR97, GPR114, and GPR126. GPR112 is specifically expressed in normal enterochromatin cells and gastrointestinal neuroendocrine carcinoma cells, but its biological function is unknown. 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 1039791003  822 LCLFSTIITYIlnhsSIHVSRKGW--HMLLNLCFHMAMTSAVFVGGVTLTNYQM--VCQAVGITLHYSSLSSLLWMGVKA 897
Cdd:cd15997     17 IFLGITLVTYL----AFEKLRRDYpsKILINLCTALLMLNLVFLLNSWLSSFNNygLCITVAAFLHYFLLASFTWMGLEA 92

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  898 --------RVLHKELswrappleegeaappgPRPMLRFYLIAGGIPLIICGITAAVNIHNYRDHS---------PYCWLv 960
Cdd:cd15997     93 vhmyfalvKVFNIYI----------------PNYILKFCIAGWGIPAVVVALVLAINKDFYGNELssdslhpstPFCWI- 155

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  961 wrPSLGAFYIPV----ALILPITWIYFLCAGLHLRSHVAQNPKQVSAGVgtpaPPEDGDGVYSPGVQLGalMTTHFLYLA 1036
Cdd:cd15997    156 --QDDVVFYISVvayfCLIFLCNISMFITVLIQIRSMKAKKPSRNWKQG----FLHDLKSVASLTFLLG--LTWGFAFFA 227

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1039791003 1037 mwacgalavsqrWLP-RVVCSCLYGVAASALGLFVFTHHCARRRDVRASWRA 1087
Cdd:cd15997    228 ------------WGPvRIFFLYLFSICNTLQGFFIFVFHCLMKENVRKQWRI 267

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 1039791003  812 VVYPCTALLLLCLFSTIityilnHSSIHVSRKgwhmllNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLSSLL 891
Cdd:cd15991     16 LVALLITFILLVLIRTL------RSNLHSIHK------NLVAALFFSELIFLIGINQTENPFVCTVVAILLHYFYMSTFA 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  892 WMGVKARVLHKELSwrappleEGEAAPPGPrpmLRFYLIAG-GIPLIICGITAAVNIHNYrDHSPYCWLVWRPSL-GAFY 969
Cdd:cd15991     84 WMFVEGLHIYRMLT-------EVRNINTGH---MRFYYVVGwGIPAIITGLAVGLDPQGY-GNPDFCWLSVQDTLiWSFA 152

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  970 IPVALILPITWIYFLCAglhlrshvaqnpkqVSAGVGTPAPPEDGDGVYSpgvqlgaLMTTHFLYL----AMWACGALAV 1045
Cdd:cd15991    153 GPIGIVVIINTVIFVLA--------------AKASCGRRQRYFEKSGVIS-------MLRTAFLLLllisATWLLGLMAV 211

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|..
gi 1039791003 1046 SQRWLprvVCSCLYGVAASALGLFVFTHHCARRRDVRASWRA 1087
Cdd:cd15991    212 NSDTL---SFHYLFAIFSCLQGIFIFFFHCIFNKEVRKHLKN 250

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 1039791003  821 LLCLFSTIITYILnHSSIHVSRKGWHMllNLCFHMAMTSAVFVGGVTLTNYQMVCQAVGITLHYSSLSSLLWM---GVKA 897
Cdd:cd15252     16 LVCLAICIFTFWF-FRGLQSDRTTIHK--NLCISLFLAELVFLIGINTTTNKIFCSVIAGLLHYFFLAAFAWMfieGIQL 92

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  898 RVLHKELSWRAPPLEEgeaappgprpmlRFYLIAGGIPLIICGITAAVNIHNYrDHSPYCWL------VWrpslgAFYIP 971
Cdd:cd15252     93 YLMLVEVFENEGSRHK------------NFYIFGYGSPAVIVGVSAALGYRYY-GTTKVCWLstenyfIW-----SFIGP 154

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791003  972 VALILPITWIYFLCAGLHLRSHVAQNPKQVSAGVGTPAppedgdgvyspgVQLGALMTThFLYLAMWACGALAVSQRwlp 1051
Cdd:cd15252    155 ATLIILLNLIFLGVAIYKMFRHTAGLKPEVSCLENIRS------------WARGAIALL-FLLGLTWIFGVLHINHA--- 218