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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1039791005 806 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQA 877
Cdd:cd15998     1 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHIAMTSAVFAGGITLTNYQMVCQA 72

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 114 DLPEPPDPglLPNgTITLLLSNNKITGLRNgSFLGLSLLEKLDLRSNVISTVqPGAFLGLGELKRLDLSNNRIGCLTSet 193
Cdd:COG4886   173 DLPEELGN--LTN-LKELDLSNNQITDLPE-PLGNLTNLEELDLSGNQLTDL-PEPLANLTNLETLDLSNNQLTDLPE-- 245

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1039791005 194 FQGLPRLLRLNISGNIYSSLQPGVfdELPALKIVDFGTEFLTcDCRLRWLLPWARNHSLQLSERTL 259
Cdd:COG4886   246 LGNLTNLEELDLSNNQLTDLPPLA--NLTNLKTLDLSNNQLT-DLKLKELELLLGLNSLLLLLLLL 308

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 1039791005 751 PMAAWWNQ--DGPGGWSSEGCRLRYSQPNVSSLYCQHLGNVAVL 792
Cdd:pfam01825   1 PQCVFWDFtnSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1039791005 806 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQA 877
Cdd:cd15998     1 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHIAMTSAVFAGGITLTNYQMVCQA 72

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 130 TLLLSNNKITGLRNgSFLGLSLLEKLDLRSNVISTVqPGAFLGLGELKRLDLSNNRIGCLtSETFQGLPRLLRLNISGNI 209
Cdd:COG4886   140 ELDLSNNQLTDLPE-PLGNLTNLKSLDLSNNQLTDL-PEELGNLTNLKELDLSNNQITDL-PEPLGNLTNLEELDLSGNQ 216

                          90
                  ....*....|....*....
gi 1039791005 210 YSSLqPGVFDELPALKIVD 228
Cdd:COG4886   217 LTDL-PEPLANLTNLETLD 234

Leucine rich repeat;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1039791005 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 1039791005 131 LLLSNNKITGLRNgsFLGLSLLEKLDLRSNVISTV---------------------------QPGAFLGLGE-LKRLDLS 182
Cdd:cd21340    51 LYLQNNQIEKIEN--LENLVNLKKLYLGGNRISVVeglenltnleelhienqrlppgekltfDPRSLAALSNsLRVLNIS 128

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1039791005 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 1039791005 751 PMAAWWNQ--DGPGGWSSEGCRLRYSQPNVSSLYCQHLGNVAVL 792
Cdd:pfam01825   1 PQCVFWDFtnSTTGRWSTEGCTTVSLNDTHTVCSCNHLTSFAVL 44

Leucine rich repeat C-terminal domain;

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1039791005  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 1039791005 299 VVFQGDRLPFQCSASYLGNDTRIHWYHNGapMESDEQAGIVLAENLIHdctfiTSELTLSHIGVWASGEWECSVSTVQGN 378
Cdd:pfam00047   7 TVLEGDSATLTCSASTGSPGPDVTWSKEG--GTLIESLKVKHDNGRTT-----QSSLLISNVTKEDAGTYTCVVNNPGGS 79

                  ....*..
gi 1039791005 379 TSKKVEI 385
Cdd:pfam00047  80 ATLSTSL 86

Immunoglobulin domain of Tie2 tyrosine kinase; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig) domain of Tie2 tyrosine kinase. The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Tie2 contains three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2-Tie2 recognition is similar to antibody-protein antigen recognition, including the location of the ligand-binding site within the Ig fold. 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. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structures of the Tie2 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1039791005 338 IVLAENLIHDCTFITSELTLSHIGVWASGEWECSVSTVQGNTSKKVEI 385
Cdd:cd20964    45 VLHPKDFNHTPHRSVAEFTIHRLLPPDSGVWVCSVNTVAGMVEKPFNI 92

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1039791005 806 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQA 877
Cdd:cd15998     1 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHIAMTSAVFAGGITLTNYQMVCQA 72

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1039791005 806 GAGLHPVVYPCTALLLLCLFSTIITYILNHSSIHVSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQA 877
Cdd:cd15259     1 FELLHPVVYAGAALCLLCLLATIITYIVFHRLIRISRKGRHMLVNLCLHLLLTCVVFVGGINRTANQLVCQA 72

Leucine rich repeat;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1039791005 130 TLLLSNNKITGLRNGSFLGLSLLEKLDLRSNVISTVQPGAFLGLGELKRLDLSNNRI 186
Cdd:pfam13855   5 SLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGNRL 61

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1039791005 809 LHPVVYPCTALLLLCLFSTIITYILNHSSIhvSRKGWHMLLNLCFHMAMTSAVFVGGVTLTNYQMVCQA 877
Cdd:cd15040     4 LSIITYIGCGLSLLGLLLTIITYILFRKLR--KRKPTKILLNLCLALLLANLLFLFGINSTDNPVLCTA 70

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 114 DLPEPPDPglLPNgTITLLLSNNKITGLRNgSFLGLSLLEKLDLRSNVISTVqPGAFLGLGELKRLDLSNNRIGCLTSet 193
Cdd:COG4886   173 DLPEELGN--LTN-LKELDLSNNQITDLPE-PLGNLTNLEELDLSGNQLTDL-PEPLANLTNLETLDLSNNQLTDLPE-- 245

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1039791005 194 FQGLPRLLRLNISGNIYSSLQPGVfdELPALKIVDFGTEFLTcDCRLRWLLPWARNHSLQLSERTL 259
Cdd:COG4886   246 LGNLTNLEELDLSNNQLTDLPPLA--NLTNLKTLDLSNNQLT-DLKLKELELLLGLNSLLLLLLLL 308

Leucine rich repeat;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1039791005 175 ELKRLDLSNNRIGCLTSETFQGLPRLLRLNISGNIYSSLQPGVFDELPALKIVD 228
Cdd:pfam13855   2 NLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLPSLRYLD 55

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 130 TLLLSNNKITGLRngSFLGLSLLEKLDLRSNVISTVQPGAflGLGELKRLDLSNNRIGCLTSETFQGLPRL--LRLNISG 207
Cdd:COG4886   232 TLDLSNNQLTDLP--ELGNLTNLEELDLSNNQLTDLPPLA--NLTNLKTLDLSNNQLTDLKLKELELLLGLnsLLLLLLL 307

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 208 NIYSSLQPGVFDELPALKIVDFGTEFLTCDCRLRWLLPWARNHSLQLSERTLCAYPSALHAHALSSLQESQLRCEGALEL 287
Cdd:COG4886   308 LNLLELLILLLLLTTLLLLLLLLKGLLVTLTTLALSLSLLALLTLLLLLNLLSLLLTLLLTLGLLGLLEATLLTLALLLL 387

                  ....*
gi 1039791005 288 HTHYL 292
Cdd:COG4886   388 TLLLL 392

Domain present in hormone receptors;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1039791005  393 SYCPAErvtnNRGDFRWPRTLAGITAYQSCLQYpftsvpLSGGAPGTRASRRCDRAGRWEPG--DYSHC 459
Cdd:smart00008   3 LGCPAT----WDGIICWPQTPAGQLVEVPCPKY------FSGFSYKTGASRNCTENGGWSPPfpNYSNC 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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1039791005 409 WPRTLAGITAYQSCLQYpftsvpLSGGAPGTRASRRCDRAGRWE---PGDYSHC 459
Cdd:pfam02793  14 WPRTPAGETVEVPCPDY------FSGFDPRGNASRNCTEDGTWSehpPSNYSNC 61

Leucine rich repeat C-terminal domain;

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1039791005  234 LTCDCRLRWLLPWARNHS-LQLSERTLCAYPSALH 267
Cdd:smart00082   3 FICDCELRWLLRWLQANEhLQDPVDLRCASPSSLR 37

Leucine rich repeat;

                          10        20        30
                  ....*....|....*....|....*....|....
gi 1039791005 129 ITLLLSNNKITGLRNGSFLGLSLLEKLDLRSNVI 162
Cdd:pfam13855  28 KVLDLSNNLLTTLSPGAFSGLPSLRYLDLSGNRL 61

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 1039791005 299 VVFQGDRLPFQCSASYLGNDTRIHWYHNGapMESDEQAGIVLAENLIHdctfiTSELTLSHIGVWASGEWECSVSTVQGN 378
Cdd:pfam00047   7 TVLEGDSATLTCSASTGSPGPDVTWSKEG--GTLIESLKVKHDNGRTT-----QSSLLISNVTKEDAGTYTCVVNNPGGS 79

                  ....*..
gi 1039791005 379 TSKKVEI 385
Cdd:pfam00047  80 ATLSTSL 86

Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond to structural units consisting of a beta strand (LxxLxLxxN/CxL conserved pattern) and an alpha helix. This alignment contains 12 strands corresponding to 11 full repeats, consistent with the extent observed in the subfamily acting as Ran GTPase Activating Proteins (RanGAP1).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 130 TLLLSNNKITGLrNGSFLGLSL-----LEKLDLRSNVI-----STVQPGAFLGLGELKRLDLSNNRIGCLTSETF-QGL- 197
Cdd:cd00116   197 VLDLNNNGLTDE-GASALAETLaslksLEVLNLGDNNLtdagaAALASALLSPNISLLTLSLSCNDITDDGAKDLaEVLa 275

                          90
                  ....*....|...
gi 1039791005 198 --PRLLRLNISGN 208
Cdd:cd00116   276 ekESLLELDLRGN 288

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

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 1039791005  755 WWNQDGpGGWSSEGCRLRYSQPNVSSLYCQHLGNVAVLM 793
Cdd:smart00303   7 FWDESS-GEWSTRGCELLETNGTHTTCSCNHLTTFAVLM 44

leucine-rich repeat receptor-like protein kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039791005 113 GDLPEPPDPGLLPNgtitLLLSNNKITGLRNGSFLGLSLLEKLDLRSNVISTVQPGAFLGLGELKRLDLSNNRIGCLTSE 192
Cdd:PLN00113  466 GGLPDSFGSKRLEN----LDLSRNQFSGAVPRKLGSLSELMQLKLSENKLSGEIPDELSSCKKLVSLDLSHNQLSGQIPA 541

                          90       100
                  ....*....|....*....|...
gi 1039791005 193 TFQGLPRLLRLNISGNIYSSLQP 215
Cdd:PLN00113  542 SFSEMPVLSQLDLSQNQLSGEIP 564

Immunoglobulin domain of Tie2 tyrosine kinase; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig) domain of Tie2 tyrosine kinase. The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Tie2 contains three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2-Tie2 recognition is similar to antibody-protein antigen recognition, including the location of the ligand-binding site within the Ig fold. 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. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structures of the Tie2 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1039791005 338 IVLAENLIHDCTFITSELTLSHIGVWASGEWECSVSTVQGNTSKKVEI 385
Cdd:cd20964    45 VLHPKDFNHTPHRSVAEFTIHRLLPPDSGVWVCSVNTVAGMVEKPFNI 92