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 1720383122  661 GVSEVIQTLLEISQDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQIISNLLAEENRDKWEEAQLMGPNAKE 740
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720383122  741 --LFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPAS---GATDISFPMKGWRATGdwakvpEDRVTVSKSVFStg 815
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLDTHnfkGARFPRFPMKGERPKD------EDSVKLPPKAFK-- 152

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1720383122  816 laEADDSSVFVVGTVLYRNLGSFLALQRN-----------TTVLNSKVISVTVKP 859
Cdd:pfam16489  153 --PPDSNGTVVVVFILYRNLGSLLPPSSRydpdrrslrlpRRVVNSPVVSASVHS 205

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1720383122   412 WDEWSPWSLCSSTCGRGFRDRTRTC--RPPQFGGNPCEGPEKQTKFCNIALCP 462
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcsPPPQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1720383122   525 WQAWASWGSCSVTCGGGSQRRERVCSGP--FFGGAACQGPQDEYRQCGAQRCP 575
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPppQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1720383122   359 EWSPWSVCSSTCGEGWQTRTRFCVSSSYS---TQCSGPLREQRLCNNSAvCP 407
Cdd:smart00209    3 EWSEWSPCSVTCGGGVQTRTRSCCSPPPQnggGPCTGEDVETRACNEQP-CP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1720383122   264 WKLWSLWGECTRDCGGGLQTRTRTC-LPTLGVEGGGCEGVLEEGRLCNRKAC 314
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcSPPPQNGGGPCTGEDVETRACNEQPC 52

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 1720383122  661 GVSEVIQTLLEISQDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQIISNLLAEENRDKWEEAQLMGPNAKE 740
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720383122  741 --LFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPAS---GATDISFPMKGWRATGdwakvpEDRVTVSKSVFStg 815
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLDTHnfkGARFPRFPMKGERPKD------EDSVKLPPKAFK-- 152

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1720383122  816 laEADDSSVFVVGTVLYRNLGSFLALQRN-----------TTVLNSKVISVTVKP 859
Cdd:pfam16489  153 --PPDSNGTVVVVFILYRNLGSLLPPSSRydpdrrslrlpRRVVNSPVVSASVHS 205

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1720383122   412 WDEWSPWSLCSSTCGRGFRDRTRTC--RPPQFGGNPCEGPEKQTKFCNIALCP 462
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcsPPPQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1720383122   525 WQAWASWGSCSVTCGGGSQRRERVCSGP--FFGGAACQGPQDEYRQCGAQRCP 575
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPppQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1720383122   359 EWSPWSVCSSTCGEGWQTRTRFCVSSSYS---TQCSGPLREQRLCNNSAvCP 407
Cdd:smart00209    3 EWSEWSPCSVTCGGGVQTRTRSCCSPPPQnggGPCTGEDVETRACNEQP-CP 53

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1720383122  528 WASWGSCSVTCGGGSQRRERVCSGPFFGGAACQGPQDEYRQCGAQRC 574
Cdd:pfam00090    3 WSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

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        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1720383122  883 TCILWDETDGpsssappQLGPWSWRGCRTVPLDALRTRCLCDRLSTFAIL 932
Cdd:pfam01825    2 QCVFWDFTNS-------TTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

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
                   ....*....|....*....|....*....|....*....|....*
gi 1720383122  979 SSCVVLPLLALTWMSAVLAVTDRR--SALFQILFAVFDSLEGFVI 1021
Cdd:pfam00002  204 STLLLLPLLGITWVFGLFAFNPENtlRVVFLYLFLILNSFQGFFV 248

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 1720383122  578 HEICDEDNFGAVVWKETPAGEVAAVRCPR-----NATGLILRRCelDEEGI-AFWEPPTYIRCVSI 637
Cdd:pfam02793    1 GLGCPRTWDGILCWPRTPAGETVEVPCPDyfsgfDPRGNASRNC--TEDGTwSEHPPSNYSNCTSN 64

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20
                   ....*....|....*....|.
gi 1720383122  267 WSLWGECTRDCGGGLQTRTRT 287
Cdd:pfam19028    6 WSEWSECSVTCGGGVQTRTRT 26

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 1720383122  661 GVSEVIQTLLEISQDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQIISNLLAEENRDKWEEAQLMGPNAKE 740
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720383122  741 --LFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPAS---GATDISFPMKGWRATGdwakvpEDRVTVSKSVFStg 815
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLDTHnfkGARFPRFPMKGERPKD------EDSVKLPPKAFK-- 152

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1720383122  816 laEADDSSVFVVGTVLYRNLGSFLALQRN-----------TTVLNSKVISVTVKP 859
Cdd:pfam16489  153 --PPDSNGTVVVVFILYRNLGSLLPPSSRydpdrrslrlpRRVVNSPVVSASVHS 205

brain-specific angiogenesis inhibitors, group VII adhesion GPCRs, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all 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. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediate direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1720383122  975 ASLWSSCVVLPLLALTWMSAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVD 1042
Cdd:cd15251    186 ASLWSSCVVLPLLALTWMSAVLAMTDRRSVLFQILFAVFDSLQGFVIVMVHCILRREVQDAVKCRMGV 253

brain-specific angiogenesis inhibitor 3, a group VII adhesion GPCR, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all 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. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediates direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720383122  955 CGVSSLTLLMLVIiyVSVWRASLWSSCVVLPLLALTWMSAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQD 1034
Cdd:cd15989    208 CGVVSTTALSATT--ASNAMASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQD 285

                   ....*.
gi 1720383122 1035 AVKCRV 1040
Cdd:cd15989    286 AFRCRL 291

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 1720383122  946 VPsVTLIVGCgvsslTLLMLVIIYVSVWR--------------ASLWSSCVVLPLLALTWMSAVLAVTDRRSAlFQILFA 1011
Cdd:cd15040    156 GP-VLLIILV-----NLVIFVLVLRKLLRlsakrnkkkrkktkAQLRAAVSLFFLLGLTWIFGILAIFGARVV-FQYLFA 228

                           90       100
                   ....*....|....*....|....*
gi 1720383122 1012 VFDSLEGFVIVMVHCILRREVQDAV 1036
Cdd:cd15040    229 IFNSLQGFFIFIFHCLRNKEVRKAW 253

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1720383122   525 WQAWASWGSCSVTCGGGSQRRERVCSGP--FFGGAACQGPQDEYRQCGAQRCP 575
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPppQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1720383122   359 EWSPWSVCSSTCGEGWQTRTRFCVSSSYS---TQCSGPLREQRLCNNSAvCP 407
Cdd:smart00209    3 EWSEWSPCSVTCGGGVQTRTRSCCSPPPQnggGPCTGEDVETRACNEQP-CP 53

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1720383122  414 EWSPWSLCSSTCGRGFRDRTRT-CRPPQFGGNPCeGPEKQTKFCNIALC 461
Cdd:pfam19028    5 EWSEWSECSVTCGGGVQTRTRTvIVEPQNGGRPC-PELLERRPCNLPPC 52

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720383122   577 PHEICDEDNFGAVVWKETPAGEVAAVRCPRNATGL-----ILRRCELDEegiaFWEP--PTYIRCVSIDYRNIQ 643
Cdd:smart00008    1 TDLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGFsyktgASRNCTENG----GWSPpfPNYSNCTSNDYEELK 70

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        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1720383122  883 TCILWDETDGpsssappQLGPWSWRGCRTVPLDALRTRCLCDRLSTFAIL 932
Cdd:pfam01825    2 QCVFWDFTNS-------TTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1720383122  958 SSLTLLMLVIIYVSVwRASLWSSCVVLPLLALTWMSAVLAVTDrRSALFQILFAVFDSLEGFVIVMVHCILRREV 1032
Cdd:cd15441    172 ASCTLKRHVLEKASV-RTDLRSSFLLLPLLGATWVFGLLAVNE-DSELLHYLFAGLNFLQGLFIFLFYCIFNKKV 244

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1720383122  974 RASLWSSCVVLPLLALTWMSAVLAVTDRrSALFQILFAVFDSLEGFVIVMVHCILRREVQDA 1035
Cdd:cd15933    191 KSTAKASVVLLPILGLTWLFGVLVVNSQ-TIVFQYIFVILNSLQGLMIFLFHCVLNSEVRSA 251

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
                   ....*....|....*....|....*....|....*....|....*
gi 1720383122  979 SSCVVLPLLALTWMSAVLAVTDRR--SALFQILFAVFDSLEGFVI 1021
Cdd:pfam00002  204 STLLLLPLLGITWVFGLFAFNPENtlRVVFLYLFLILNSFQGFFV 248

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1720383122  527 AWASWGSCSVTCGGGSQRRER-VCSGPFFGGAACqGPQDEYRQCGAQRC 574
Cdd:pfam19028    5 EWSEWSECSVTCGGGVQTRTRtVIVEPQNGGRPC-PELLERRPCNLPPC 52

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1720383122   264 WKLWSLWGECTRDCGGGLQTRTRTC-LPTLGVEGGGCEGVLEEGRLCNRKAC 314
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcSPPPQNGGGPCTGEDVETRACNEQPC 52

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20
                   ....*....|....*....|.
gi 1720383122  359 EWSPWSVCSSTCGEGWQTRTR 379
Cdd:pfam19028    5 EWSEWSECSVTCGGGVQTRTR 25

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 1720383122  362 PWSVCSSTCGEGWQTRTRFCVSSSY-----STQCSGPLR--EQRLCNN 402
Cdd:pfam19030    5 PWGECSVTCGGGVQTRLVQCVQKGGgsivpDSECSAQKKppETQSCNL 52

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720383122  974 RASLWSSCVVLPLLALTWMSAVLAVtDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQ 1033
Cdd:cd15252    191 RSWARGAIALLFLLGLTWIFGVLHI-NHASVVMAYLFTVSNSLQGMFIFLFHCVLSRKVR 249

orphan adhesion receptor GPR113, member of the class B2 family of seven-transmembrane G protein-coupled receptors; GPR113 is an orphan receptor that belongs to group VI adhesion-GPCRs along with GPR110, GPR111, GPR115, and GPR116. 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. GPR113 contains a hormone binding domain and one EGF (epidermal grown factor) domain, and is primarily expressed in a subset of taste receptor cells. 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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1720383122  970 VSVWRASLwsscVVLPLLALTWMSAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRV 1040
Cdd:cd15253    203 LSIFKALL----VLTPVFGLTWGLGVATLTGESSQVSHYGFAILNAFQGVFILLFGCLMDKKVREALLKRL 269

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                           10        20
                   ....*....|....*....|.
gi 1720383122  267 WSLWGECTRDCGGGLQTRTRT 287
Cdd:pfam19028    6 WSEWSECSVTCGGGVQTRTRT 26

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1720383122  977 LWSSCVVLPLLALTWMSAVLAV-TDRRSalFQILFAVFDSLEGFVIVMVHCILRREVQDAVK 1037
Cdd:cd15991    190 LRTAFLLLLLISATWLLGLMAVnSDTLS--FHYLFAIFSCLQGIFIFFFHCIFNKEVRKHLK 249

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720383122  974 RASLWSSCVVLPLLALTWMSAvLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVK 1037
Cdd:cd15931    196 RLLTFKAVAQLFILGCTWVLG-LFQTNPVALVFQYLFTILNSLQGAFLFLVHCLLNKEVREEYI 258

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1720383122  976 SLWSSCVVLPLLALTWMSAVLAVTDRRSAlFQILFAVFDSLEGFVIVMVHCILRREVQDAVK 1037
Cdd:cd15993    189 TLRSSFLLLLLISATWLFGLLAVNNSVLA-FHYLHAILCCLQGLAVLLLFCVLNEEVQEAWK 249

Thrombospondin type 1 domain;

                           10        20
                   ....*....|....*....|...
gi 1720383122  266 LWSLWGECTRDCGGGLQTRTRTC 288
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTC 24