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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458  923 AGAPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 1002
Cdd:cd15988     1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1003 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1082
Cdd:cd15988    81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1083 LVNMLIGIIVFNKLMARDGVSDKSKKQRAG--RLSW-NLWGYGSQLCLFPKL---------PRASLWSSCVVLPLLALTW 1150
Cdd:cd15988   161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGseAEPCsSLLLKCSKCGVVSSAamssatassAMASLWSSCVVLPLLALTW 240

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|.
gi 146134458 1151 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1201
Cdd:cd15988   241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

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 146134458   605 GMSQVVRSLQELLARRTYYSGDLLFSVDILRNVTDTFKRATYVPSADDVQRFFQVVSFMVDSENKDKWDDAQQVSPGSVH 684
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458   685 --LLRVVEDFIHLVGDALKAFQSSLIVTDNLVISIQRE--PISAVSSDITFPMRGRRGmkdwvrHSEDRLFLPKEVLSLS 760
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLdtHNFKGARFPRFPMKGERP------KDEDSVKLPPKAFKPP 154

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 146134458    864 TDPHCASWDYSRadtnsGDWNTESCQTLETQAAHTRCQCQHLSTFAVLAQPPKD 917
Cdd:smart00303    1 FNPICVFWDESS-----GEWSTRGCELLETNGTHTTCSCNHLTTFAVLMDVPPI 49

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 146134458    469 WGPWNAWSLCSKTCDTGWQRRFRMC--QASGTQGYPCEGTGEEVKPCSEKRCP 519
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcsPPPQNGGGPCTGEDVETRACNEQPCP 53

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 146134458    522 HEMCRDEYVMLMTWKRAAAGEIIYNKCPPNASG-----SASRRCLLSAQgvayWGL--PSFARCISHEYRYL 586
Cdd:smart00008    2 DLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGfsyktGASRNCTENGG----WSPpfPNYSNCTSNDYEEL 69

brain-specific angiogenesis inhibitor 2, 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 146134458  923 AGAPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 1002
Cdd:cd15988     1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1003 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1082
Cdd:cd15988    81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1083 LVNMLIGIIVFNKLMARDGVSDKSKKQRAG--RLSW-NLWGYGSQLCLFPKL---------PRASLWSSCVVLPLLALTW 1150
Cdd:cd15988   161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGseAEPCsSLLLKCSKCGVVSSAamssatassAMASLWSSCVVLPLLALTW 240

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|.
gi 146134458 1151 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1201
Cdd:cd15988   241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

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 146134458   923 AGAPSVPLVIGCAVSCMALLTLLAIYAAFwRFIKSERSIILLNFCLSILASNILILVGQSRVLSKG--------VCTMTA 994
Cdd:pfam00002    1 ALSLKVIYTVGYSLSLVALLLAIAIFLLF-RKLHCTRNYIHLNLFASFILRALLFLVGDAVLFNKQdldhcswvGCKVVA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458   995 AFLHFFFLSSFCWVLTEAWQSYLA-VIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTrTKGYGTSSYCWLSLEGGLLYA 1073
Cdd:pfam00002   80 VFLHYFFLANFFWMLVEGLYLYTLlVEVFFSERKYFWWYLLIGWGVPALVVGIWAGVD-PKGYGEDDGCWLSNENGLWWI 158

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458  1074 FVGPAAVIVLVNMLIGIIVFNKLMARDGVSDKSKKQRAGRLSWnlwgygsqlclfpklprasLWSSCVVLPLLALTWMSA 1153
Cdd:pfam00002  159 IRGPILLIILVNFIIFINIVRILVQKLRETNMGKSDLKQYRRL-------------------AKSTLLLLPLLGITWVFG 219

                          250       260
                   ....*....|....*....|....*....
gi 146134458  1154 VLAMTDRR--SVLFQALFAVFNSAQGFVI 1180
Cdd:pfam00002  220 LFAFNPENtlRVVFLYLFLILNSFQGFFV 248

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 146134458    358 WEEWGSWSLCSRSCGRGSRSRMRTCV--PPQHGGKACEGPELQTKLCSMAACP 408
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspPPQNGGGPCTGEDVETRACNEQPCP 53

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 146134458   866 PHCASWDYSraDTNSGDWNTESCQTLETQAAHTRCQCQHLSTFAVL 911
Cdd:pfam01825    1 PQCVFWDFT--NSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 146134458    469 WGPWNAWSLCSKTCDTGWQRRFRMC--QASGTQGYPCEGTGEEVKPCSEKRCP 519
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCcsPPPQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 146134458   305 EWSPWSVCSLTCGQGLQVRTRSCVS-SPYGTLCSGPLRETRPCN 347
Cdd:pfam00090    2 PWSPWSPCSVTCGKGIQVRQRTCKSpFPGGEPCTGDDIETQACK 45

Domain present in hormone receptors;

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 146134458    522 HEMCRDEYVMLMTWKRAAAGEIIYNKCPPNASG-----SASRRCLLSAQgvayWGL--PSFARCISHEYRYL 586
Cdd:smart00008    2 DLGCPATWDGIICWPQTPAGQLVEVPCPKYFSGfsyktGASRNCTENGG----WSPpfPNYSNCTSNDYEEL 69

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 146134458   470 GPWNAWSLCSKTCDTGWQRRFRMCQASGTQGYPCEGTGEEVKPCSEKRC 518
Cdd:pfam00090    1 SPWSPWSPCSVTCGKGIQVRQRTCKSPFPGGEPCTGDDIETQACKMDKC 49

sporozoite surface protein 2 (SSP2); Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 146134458  350 ATCpvhGVWEEWgswSLCSRSCGRGSRSRMRtcvPPQHGGkaCEgPELQTKlCSMAACPVE 410
Cdd:PTZ00441  238 ASC---GPWDEW---TPCSVTCGKGTHSRSR---PILHEG--CT-THMVEE-CEEEECPVE 285

brain-specific angiogenesis inhibitor 2, 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 146134458  923 AGAPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFL 1002
Cdd:cd15988     1 TGSPSVPLMIGCAVSCMALLILLAIYAAFWRFIRSERSIILLNFCLSILASNILILVGQSQTLSKGVCTMTAAFLHFFFL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1003 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIV 1082
Cdd:cd15988    81 SSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTASYCWLSLEGGLLYAFVGPAAVIV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1083 LVNMLIGIIVFNKLMARDGVSDKSKKQRAG--RLSW-NLWGYGSQLCLFPKL---------PRASLWSSCVVLPLLALTW 1150
Cdd:cd15988   161 LVNMLIGIIVFNKLMSRDGISDKSKKQRAGseAEPCsSLLLKCSKCGVVSSAamssatassAMASLWSSCVVLPLLALTW 240

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|.
gi 146134458 1151 MSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGV 1201
Cdd:cd15988   241 MSAVLAMTDRRSILFQVLFAVFNSVQGFVIITVHCFLRREVQDVVKCQMGG 291

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 146134458  921 ELAGAPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFF 1000
Cdd:cd15989     1 ESSGTPSVTLIVGCGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKGICTMTTAFLHFF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1001 FLSSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAV 1080
Cdd:cd15989    81 FLASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVAISMGFTKAKGYGTPHYCWLSLEGGLLYAFVGPAAA 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1081 IVLVNMLIGIIVFNKLMARDGVSDKSKKQRAGRLS---------WNLWGYGSQLCLFPKLPR---ASLWSSCVVLPLLAL 1148
Cdd:cd15989   161 VVLVNMVIGILVFNKLVSRDGILDKKLKHRAGQMSephsgltlkCAKCGVVSTTALSATTASnamASLWSSCVVLPLLAL 240

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|.
gi 146134458 1149 TWMSAVLAMTDRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQM 1199
Cdd:cd15989   241 TWMSAVLAMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQDAFRCRL 291

Adhesion GPCR B N-terminal region; This region is found at the N-terminus of various adhesion G-protein coupled receptor B proteins. This region contains 10 cysteine residues that probably form disulphide bonds.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458    26 SACSALASGVLYGAFSLQDLFPTIASGCSWTLENPDPTKYSLYLRFNRQEQVCTHFAPRLLPLDHYLVNFTclrpgpeea 105
Cdd:pfam19188    1 DPCSTLVQGVLYGSFSLRDLFPTNASGCSWTLENPDPTKYTLYLKFTKPTQSCLPFSPRLLQFDHYLENTT--------- 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458   106 taraESEVGRPeeeeeeaaAAASGLELCGGSGPFTFLHFDKNFVQLCLSAEPSEAPRLLAPAALAFRFVEVLLINNNNSS 185
Cdd:pfam19188   72 ----RTYLGRE--------SFDEVVELCDASSPFSFLEFDKNFVQLCLLAEPRGDPESVVPGPSGDFKVEVLVINNENPS 139

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 146134458   186 QFTCGVLCRWSEECGRAA--GRACGFAQPGCSCPGEAG 221
Cdd:pfam19188  140 QFTCGVLCRWLEECLSAStsSRPCGIMQTPCICPGTVP 177

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 146134458  932 IGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 1011
Cdd:cd15040    10 IGCGLSLLGLLLTIITYILFRKLRKRKPTKILLNLCLALLLANLLFLFGINSTDNPVLCTAVAALLHYFLLASFMWMLVE 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1012 AWQSYLAVIGRMRT--RLVRKRFLCLGWGLPALVVAVSVGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIG 1089
Cdd:cd15040    90 ALLLYLRLVKVFGTypRHFILKYALIGWGLPLIIVIITLAVDPDSYGNSSGYCWLSNGNGLYYAFLGPVLLIILVNLVIF 169

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1090 IIVFNKLMARDGVSDKSKKQRAgrlswnlwgygsqlclfpklpRASLWSSCVVLPLLALTWMSAVLAMTDRRSVlFQALF 1169
Cdd:cd15040   170 VLVLRKLLRLSAKRNKKKRKKT---------------------KAQLRAAVSLFFLLGLTWIFGILAIFGARVV-FQYLF 227

                         250       260
                  ....*....|....*....|....
gi 146134458 1170 AVFNSAQGFVITAVHCFLRREVQD 1193
Cdd:cd15040   228 AIFNSLQGFFIFIFHCLRNKEVRK 251

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 146134458  931 VIGCAVSCMALLTLLAIYAAFWRFIKSeRSIILLNFCLSILASNILILVGQSRVLSKG--VCTMTAAFLHFFFLSSFCWV 1008
Cdd:cd13952     9 YIGCSLSLVGLLLTIITYLLFPKLRNL-RGKILINLCLSLLLAQLLFLIGQLLTSSDRpvLCKALAILLHYFLLASFFWM 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1009 LTEAWQSYLAVIGRMRTRLvRKRFL---CLGWGLPALVVAVSVGFTRT----KGYGTSSYCWLSLEGGLLYAFVGPAAVI 1081
Cdd:cd13952    88 LVEAFDLYRTFVKVFGSSE-RRRFLkysLYGWGLPLLIVIITAIVDFSlygpSPGYGGEYCWLSNGNALLWAFYGPVLLI 166

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1082 VLVNMLIGIIVFNKLMARDGVSDKSKKqragrlswnlwgygsqlclfPKLPRASLWSSCVVLPLLALTWMSAVLAMTDRR 1161
Cdd:cd13952   167 LLVNLVFFILTVRILLRKLRETPKQSE--------------------RKSDRKQLRAYLKLFPLMGLTWIFGILAPFVGG 226

                         250       260       270
                  ....*....|....*....|....*....|.
gi 146134458 1162 SVLFQALFAVFNSAQGFVITAVHCFLRREVQ 1192
Cdd:cd13952   227 SLVFWYLFDILNSLQGFFIFLIFCLKNKEVR 257

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 146134458   605 GMSQVVRSLQELLARRTYYSGDLLFSVDILRNVTDTFKRATYVPSADDVQRFFQVVSFMVDSENKDKWDDAQQVSPGSVH 684
Cdd:pfam16489    1 GAKELARELRNATRHGPLYGGDVLTAVELLSQLFDLLATQDATLSNAFLENFVQTVSNLLDPENRESWEDLQQTERGTAA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458   685 --LLRVVEDFIHLVGDALKAFQSSLIVTDNLVISIQRE--PISAVSSDITFPMRGRRGmkdwvrHSEDRLFLPKEVLSLS 760
Cdd:pfam16489   81 tkLLRTLEEYALLLAQNMKYLTPFTIVTPNIVLSVDRLdtHNFKGARFPRFPMKGERP------KDEDSVKLPPKAFKPP 154

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 146134458  932 IGCAVSCMALLtLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 1011
Cdd:cd15438    10 VGLSVSLFCLF-LCILTFLFCRSIRGTRNTIHLHLCLSLFLAHLIFLLGINNTNNQVACAVVAGLLHYFFLAAFCWMSLE 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1012 AWQSYLAVIGRMRTRLVRKRFLCL-GWGLPALVVAVSVGFTrTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIGI 1090
Cdd:cd15438    89 GVELYLMVVQVFNTQSLKKRYLLLiGYGVPLVIVAISAAVN-SKGYGTQRHCWLSLERGFLWSFLGPVCLIILVNAIIFV 167

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1091 IVFNKLMAR----DGVSDKSKKQRAGRLSwnlwgYGSQLClfpklpraslwsscvvlpLLALTWMSAVLAMTDrRSVLFQ 1166
Cdd:cd15438   168 ITVWKLAEKfssiNPDMEKLRKIRALTIT-----AIAQLC------------------ILGCTWIFGFFQFSD-STLVMS 223

                         250       260       270
                  ....*....|....*....|....*....|....*...
gi 146134458 1167 ALFAVFNSAQGFVITAVHCFLRREV-QDVVKCQMGVCR 1203
Cdd:cd15438   224 YLFTILNSLQGLFIFLLHCLLSKQVrEEYSRWLCAIAR 261

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 146134458  932 IGCAVS--CM--ALLTLLaiyaaFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCW 1007
Cdd:cd15439    10 VGLIISllCLflAILTFL-----LCRSIRNTSTSLHLQLSLCLFLADLLFLVGIDRTDNKVLCSIIAGFLHYLFLACFAW 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1008 VLTEAWQSYLAV-----IGRMRTRLVRKRFLCL-GWGLPALVVAVSVGfTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVI 1081
Cdd:cd15439    85 MFLEAVHLFLTVrnlkvVNYFSSHRFKKRFMYPvGYGLPAVIVAISAA-VNPQGYGTPKHCWLSMEKGFIWSFLGPVCVI 163

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1082 VLVNMLIGIIVFNKLmardgvsdkskKQRAGRLSWNLwgygSQLclfpKLPRASLWSSCVVLPLLALTWMSAVLAMTDRR 1161
Cdd:cd15439   164 IVINLVLFCLTLWIL-----------REKLSSLNAEV----STL----KNTRLLTFKAIAQLFILGCTWILGLFQVGPVA 224

                         250       260       270
                  ....*....|....*....|....*....|..
gi 146134458 1162 SVLfQALFAVFNSAQGFVITAVHCFLRREVQD 1193
Cdd:cd15439   225 TVM-AYLFTITNSLQGVFIFLVHCLLNRQVRE 255

Latrophilins, member of the class B2 family of seven-transmembrane G protein-coupled receptors; Latrophilins (also called lectomedins or latrotoxin receptors) belong to Group I adhesion GPCRs, which also include ETL (EGF-TM7-latrophilin-related protein). These receptors are a member of the adhesion family (subclass B2) that belongs to the class B GPCRs. Three subtypes of latrophilins have been identified: LPH1 (latrophilin-1), LPH2, and LPH3. The latrophilin-1 is a brain-specific calcium-independent receptor of alpha-latrotoxin, a potent presynaptic neurotoxin from the venom of the black widow spider that induces massive neurotransmitter release from sensory and motor neurons as well as endocrine cells, leading to nerve-terminal degeneration. Latrophilin-2 and -3, although sharing strong sequence homology to latrophilin-1, do not bind alpha-latrotoxin. While latrophilin-3 is also brain specific, latrophilin-2 is ubiquitously distributed. The endogenous ligands for these two receptors are unknown. ETL, a seven transmembrane receptor containing EGF-like repeats is highly expressed in heart, where developmentally regulated, as well as in normal smooth cells. The function of the ETL is unknown. All adhesion GPCRs possess large N-terminal extracellular domains containing multiple structural motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, coupled to a seven-transmembrane domain. In addition, almost all adhesion receptors, except GPR123, contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain that undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif located immediately N-terminal to the first transmembrane region, to generate N- and C-terminal fragments (NTF and CTF), which may serve important biological functions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458  932 IGCAVSCMALLTLLAIYAaFWRFIKSERSIILLNFCLSILASNILILVGQSRVLSKGVCTMTAAFLHFFFLSSFCWVLTE 1011
Cdd:cd15436    10 VGIVISLVCLLICIFTFC-FFRGLQTDRNTIHKNLCINLFIAELLFLIGINRTQYTIACPIFAGLLHFFFLAAFCWLCLE 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1012 AWQSYLAVIGRMRTRLVRKRFLCL-GWGLPALVVAVSVGFTrTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIGI 1090
Cdd:cd15436    89 GVQLYLLLVEVFESEYSRRKYFYLcGYSFPALVVAVSAAID-YRSYGTEKACWLRVDNYFIWSFIGPVTFVITLNLVFLV 167

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134458 1091 IVFNKLMARDGVsdksKKQRAGRLSwNL--WGYGSQLCLFpklpraslwsscvvlpLLALTWMSAVLAMtDRRSVLFQAL 1168
Cdd:cd15436   168 ITLHKMVSHSDL----LKPDSSRLD-NIksWALGAIALLF----------------LLGLTWSFGLMFI-NEESVVMAYL 225