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Proteinase-activated receptor 4 (PAR-4) (Coagulation factor II receptor-like 3) (Thrombin receptor-like 3)

 PAR4_HUMAN              Reviewed;         385 AA.
Q96RI0; O76067; Q6DK42;
27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
17-OCT-2006, sequence version 3.
23-FEB-2022, entry version 177.
RecName: Full=Proteinase-activated receptor 4;
Short=PAR-4;
AltName: Full=Coagulation factor II receptor-like 3;
AltName: Full=Thrombin receptor-like 3;
Flags: Precursor;
Name=F2RL3; Synonyms=PAR4;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-120.
PubMed=9722561; DOI=10.1074/jbc.273.36.23290;
Kahn M.L., Hammes S.R., Botka C., Coughlin S.R.;
"Gene and locus structure and chromosomal localization of the protease-
activated receptor gene family.";
J. Biol. Chem. 273:23290-23296(1998).
[2]
NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-120.
PubMed=9716134; DOI=10.1038/29325;
Kahn M.L., Zheng Y.-W., Huang W., Bigornia V., Zeng D., Moff S.,
Farese R.V. Jr., Tam C., Coughlin S.R.;
"A dual thrombin receptor system for platelet activation.";
Nature 394:690-694(1998).
[3]
NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF ARG-47 AND ARG-68, AND VARIANT
THR-120.
TISSUE=Lymphoma;
PubMed=9618465; DOI=10.1073/pnas.95.12.6642;
Xu W.-F., Andersen H., Whitmore T.E., Presnell S.R., Yee D.P., Ching A.,
Gilbert T., Davie E.W., Foster D.C.;
"Cloning and characterization of human protease-activated receptor 4.";
Proc. Natl. Acad. Sci. U.S.A. 95:6642-6646(1998).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Lung;
King M.M., Aronstam R.S., Sharma S.V.;
"cDNA clones of human proteins involved in signal transduction sequenced by
the Guthrie cDNA resource center (www.cdna.org).";
Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-296 AND LEU-310.
SeattleSNPs variation discovery resource;
Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project:
the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
FUNCTION.
PubMed=10079109; DOI=10.1172/jci6042;
Kahn M.L., Nakanishi-Matsui M., Shapiro M.J., Ishihara H., Coughlin S.R.;
"Protease-activated receptors 1 and 4 mediate activation of human platelets
by thrombin.";
J. Clin. Invest. 103:879-887(1999).
-!- FUNCTION: Receptor for activated thrombin or trypsin coupled to G
proteins that stimulate phosphoinositide hydrolysis. May play a role in
platelets activation. {ECO:0000269|PubMed:10079109}.
-!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
-!- TISSUE SPECIFICITY: Widely expressed, with highest levels in lung,
pancreas, thyroid, testis and small intestine. Not expressed in brain,
kidney, spinal cord and peripheral blood leukocytes. Also detected in
platelets.
-!- PTM: A proteolytic cleavage generates a new N-terminus that functions
as a tethered ligand.
-!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
{ECO:0000255|PROSITE-ProRule:PRU00521}.
-!- WEB RESOURCE: Name=SeattleSNPs;
URL="http://pga.gs.washington.edu/data/f2rl3/";
---------------------------------------------------------------------------
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EMBL; AF080214; AAC28860.1; -; mRNA.
EMBL; AF055917; AAC25699.1; -; mRNA.
EMBL; AY431102; AAR08487.1; -; mRNA.
EMBL; AF384819; AAK61908.1; -; Genomic_DNA.
EMBL; BC074782; AAH74782.2; -; mRNA.
CCDS; CCDS12350.1; -.
RefSeq; NP_003941.2; NM_003950.3.
PDB; 2ZPK; X-ray; 1.80 A; P/Q=46-53.
PDB; 3QDZ; X-ray; 2.80 A; E/F=39-47.
PDBsum; 2ZPK; -.
PDBsum; 3QDZ; -.
SMR; Q96RI0; -.
BioGRID; 114481; 3.
ELM; Q96RI0; -.
STRING; 9606.ENSP00000248076; -.
BindingDB; Q96RI0; -.
ChEMBL; CHEMBL4691; -.
DrugBank; DB11300; Thrombin.
GuidetoPHARMACOLOGY; 350; -.
GlyGen; Q96RI0; 1 site.
iPTMnet; Q96RI0; -.
PhosphoSitePlus; Q96RI0; -.
BioMuta; F2RL3; -.
DMDM; 116242700; -.
jPOST; Q96RI0; -.
MassIVE; Q96RI0; -.
PaxDb; Q96RI0; -.
PeptideAtlas; Q96RI0; -.
PRIDE; Q96RI0; -.
ProteomicsDB; 77962; -.
ABCD; Q96RI0; 2 sequenced antibodies.
Antibodypedia; 14245; 405 antibodies from 33 providers.
DNASU; 9002; -.
Ensembl; ENST00000248076; ENSP00000248076; ENSG00000127533.
GeneID; 9002; -.
KEGG; hsa:9002; -.
MANE-Select; ENST00000248076.4; ENSP00000248076.2; NM_003950.4; NP_003941.2.
UCSC; uc002nfa.4; human.
CTD; 9002; -.
DisGeNET; 9002; -.
GeneCards; F2RL3; -.
HGNC; HGNC:3540; F2RL3.
HPA; ENSG00000127533; Tissue enhanced (adipose tissue, lung, thyroid gland).
MIM; 602779; gene.
neXtProt; NX_Q96RI0; -.
OpenTargets; ENSG00000127533; -.
PharmGKB; PA27949; -.
VEuPathDB; HostDB:ENSG00000127533; -.
eggNOG; ENOG502QU4Y; Eukaryota.
GeneTree; ENSGT00970000193405; -.
HOGENOM; CLU_009579_8_2_1; -.
InParanoid; Q96RI0; -.
OMA; GMGTHSS; -.
OrthoDB; 995441at2759; -.
PhylomeDB; Q96RI0; -.
TreeFam; TF350010; -.
PathwayCommons; Q96RI0; -.
Reactome; R-HSA-375276; Peptide ligand-binding receptors.
Reactome; R-HSA-416476; G alpha (q) signalling events.
Reactome; R-HSA-456926; Thrombin signalling through proteinase activated receptors (PARs).
SignaLink; Q96RI0; -.
SIGNOR; Q96RI0; -.
BioGRID-ORCS; 9002; 5 hits in 1043 CRISPR screens.
EvolutionaryTrace; Q96RI0; -.
GeneWiki; F2RL3; -.
GenomeRNAi; 9002; -.
Pharos; Q96RI0; Tchem.
PRO; PR:Q96RI0; -.
Proteomes; UP000005640; Chromosome 19.
RNAct; Q96RI0; protein.
Bgee; ENSG00000127533; Expressed in adipose tissue and 102 other tissues.
ExpressionAtlas; Q96RI0; baseline and differential.
GO; GO:0005576; C:extracellular region; TAS:Reactome.
GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
GO; GO:0005886; C:plasma membrane; IDA:HPA.
GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
GO; GO:0015057; F:thrombin-activated receptor activity; TAS:ProtInc.
GO; GO:0007596; P:blood coagulation; TAS:ProtInc.
GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; TAS:ProtInc.
GO; GO:0030168; P:platelet activation; IDA:UniProtKB.
GO; GO:0060155; P:platelet dense granule organization; IC:BHF-UCL.
GO; GO:0051482; P:positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway; IBA:GO_Central.
GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:BHF-UCL.
GO; GO:0035025; P:positive regulation of Rho protein signal transduction; IBA:GO_Central.
GO; GO:0009611; P:response to wounding; TAS:ProtInc.
GO; GO:0007165; P:signal transduction; TAS:ProtInc.
InterPro; IPR000276; GPCR_Rhodpsn.
InterPro; IPR017452; GPCR_Rhodpsn_7TM.
InterPro; IPR003944; Prot_act_rcpt_4.
InterPro; IPR003912; Protea_act_rcpt.
Pfam; PF00001; 7tm_1; 1.
PRINTS; PR00237; GPCRRHODOPSN.
PRINTS; PR01428; PROTEASEAR.
PRINTS; PR01430; PROTEASEAR4.
PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
1: Evidence at protein level;
3D-structure; Blood coagulation; Cell membrane; Disulfide bond;
G-protein coupled receptor; Glycoprotein; Hemostasis; Membrane; Receptor;
Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix.
SIGNAL 1..17
/evidence="ECO:0000255"
PROPEP 18..47
/note="Removed for receptor activation"
/evidence="ECO:0000250"
/id="PRO_0000012762"
CHAIN 48..385
/note="Proteinase-activated receptor 4"
/id="PRO_0000012763"
TOPO_DOM 48..82
/note="Extracellular"
/evidence="ECO:0000255"
TRANSMEM 83..103
/note="Helical; Name=1"
/evidence="ECO:0000255"
TOPO_DOM 104..108
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 109..129
/note="Helical; Name=2"
/evidence="ECO:0000255"
TOPO_DOM 130..151
/note="Extracellular"
/evidence="ECO:0000255"
TRANSMEM 152..172
/note="Helical; Name=3"
/evidence="ECO:0000255"
TOPO_DOM 173..192
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 193..213
/note="Helical; Name=4"
/evidence="ECO:0000255"
TOPO_DOM 214..247
/note="Extracellular"
/evidence="ECO:0000255"
TRANSMEM 248..268
/note="Helical; Name=5"
/evidence="ECO:0000255"
TOPO_DOM 269..283
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 284..304
/note="Helical; Name=6"
/evidence="ECO:0000255"
TOPO_DOM 305..319
/note="Extracellular"
/evidence="ECO:0000255"
TRANSMEM 320..343
/note="Helical; Name=7"
/evidence="ECO:0000255"
TOPO_DOM 344..385
/note="Cytoplasmic"
/evidence="ECO:0000255"
REGION 21..42
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
REGION 362..385
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
COMPBIAS 21..38
/note="Polar residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
SITE 47..48
/note="Cleavage; by thrombin or trypsin"
/evidence="ECO:0000250"
CARBOHYD 56
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
DISULFID 149..228
/evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
VARIANT 120
/note="A -> T (in dbSNP:rs773902)"
/evidence="ECO:0000269|PubMed:9618465,
ECO:0000269|PubMed:9716134, ECO:0000269|PubMed:9722561"
/id="VAR_028300"
VARIANT 215
/note="R -> Q (in dbSNP:rs2230799)"
/id="VAR_028301"
VARIANT 296
/note="F -> V (in dbSNP:rs2227346)"
/evidence="ECO:0000269|Ref.5"
/id="VAR_012852"
VARIANT 310
/note="P -> L (in dbSNP:rs2227376)"
/evidence="ECO:0000269|Ref.5"
/id="VAR_012853"
MUTAGEN 47
/note="R->A: No proteolytic cleavage (by thrombin or
trypsin)."
/evidence="ECO:0000269|PubMed:9618465"
MUTAGEN 68
/note="R->A: No effect on receptor activation."
/evidence="ECO:0000269|PubMed:9618465"
STRAND 44..46
/evidence="ECO:0007829|PDB:3QDZ"
SEQUENCE 385 AA; 41133 MW; FACE32F10D5C561E CRC64;
MWGRLLLWPL VLGFSLSGGT QTPSVYDESG STGGGDDSTP SILPAPRGYP GQVCANDSDT
LELPDSSRAL LLGWVPTRLV PALYGLVLVV GLPANGLALW VLATQAPRLP STMLLMNLAA
ADLLLALALP PRIAYHLRGQ RWPFGEAACR LATAALYGHM YGSVLLLAAV SLDRYLALVH
PLRARALRGR RLALGLCMAA WLMAAALALP LTLQRQTFRL ARSDRVLCHD ALPLDAQASH
WQPAFTCLAL LGCFLPLLAM LLCYGATLHT LAASGRRYGH ALRLTAVVLA SAVAFFVPSN
LLLLLHYSDP SPSAWGNLYG AYVPSLALST LNSCVDPFIY YYVSAEFRDK VRAGLFQRSP
GDTVASKASA EGGSRGMGTH SSLLQ


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Pathways :
WP94: Signaling of Hepatocyte Growth Factor Receptor
WP444: Signaling of Hepatocyte Growth Factor Receptor
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WP193: Signaling of Hepatocyte Growth Factor Receptor
WP313: Signaling of Hepatocyte Growth Factor Receptor
WP1162: Signaling of Hepatocyte Growth Factor Receptor
WP927: Signaling of Hepatocyte Growth Factor Receptor
WP1206: Signaling of Hepatocyte Growth Factor Receptor
WP810: Signaling of Hepatocyte Growth Factor Receptor
WP1183: Toll-like receptor signaling pathway
WP2197: Endothelin
WP75: Toll-like receptor signaling pathway
WP1004: Kit Receptor Signaling Pathway
WP147: Kit Receptor Signaling Pathway
WP362: TGF-beta Receptor Signaling Pathway
WP926: TGF-beta Receptor Signaling Pathway
WP1025: B Cell Receptor Signaling Pathway
WP1869: Neuroransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
WP1249: EPO Receptor Signaling
WP2292: Chemokine signaling pathway
WP780: T Cell Receptor Signaling Pathway
WP1309: Toll-like receptor signaling pathway
WP2355: Corticotropin-releasing hormone

Related Genes :
[F2RL3 PAR4] Proteinase-activated receptor 4 (PAR-4) (Coagulation factor II receptor-like 3) (Thrombin receptor-like 3)
[F2RL1 GPR11 PAR2] Proteinase-activated receptor 2 (PAR-2) (Coagulation factor II receptor-like 1) (G-protein coupled receptor 11) (Thrombin receptor-like 1) [Cleaved into: Proteinase-activated receptor 2, alternate cleaved 1; Proteinase-activated receptor 2, alternate cleaved 2]
[F2rl1 Gpcr11 Gpr11 Par2] Proteinase-activated receptor 2 (PAR-2) (Coagulation factor II receptor-like 1) (G-protein coupled receptor 11) (Thrombin receptor-like 1)
[F2rl1 Par2] Proteinase-activated receptor 2 (PAR-2) (Coagulation factor II receptor-like 1) (Thrombin receptor-like 1)
[F2RL1 PAR2] Proteinase-activated receptor 2 (PAR-2) (Coagulation factor II receptor-like 1) (Thrombin receptor-like 1)
[F2rl3 Par4] Proteinase-activated receptor 4 (PAR-4) (Coagulation factor II receptor-like 3) (Thrombin receptor-like 3)
[F2rl3 Par4] Proteinase-activated receptor 4 (PAR-4) (Coagulation factor II receptor-like 3) (Thrombin receptor-like 3)
[F2] Prothrombin (EC 3.4.21.5) (Coagulation factor II) [Cleaved into: Activation peptide fragment 1; Activation peptide fragment 2; Thrombin light chain; Thrombin heavy chain]
[AHK4 CRE1 RAW1 WOL At2g01830 T23K3.2] Histidine kinase 4 (EC 2.7.13.3) (Arabidopsis histidine kinase 4) (AtHK4) (Cytokinin receptor CYTOKININ RESPONSE 1) (AtCRE1) (Cytokinin receptor CRE1) (Phosphoprotein phosphatase AHK4) (EC 3.1.3.16) (Protein AUTHENTIC HIS-KINASE 4) (Protein ROOT AS IN WOL 1) (Protein WOODEN LEG)
[F7] Coagulation factor VII (EC 3.4.21.21) (Proconvertin) (Serum prothrombin conversion accelerator) (SPCA) (Eptacog alfa) [Cleaved into: Factor VII light chain; Factor VII heavy chain]
[F10] Coagulation factor X (EC 3.4.21.6) (Stuart factor) (Stuart-Prower factor) [Cleaved into: Factor X light chain; Factor X heavy chain; Activated factor Xa heavy chain]
[F10] Coagulation factor X (EC 3.4.21.6) (Stuart factor) [Cleaved into: Factor X light chain; Factor X heavy chain; Activated factor Xa heavy chain]
[F10] Coagulation factor X (EC 3.4.21.6) (Stuart factor) [Cleaved into: Factor X light chain; Factor X heavy chain; Activated factor Xa heavy chain]
[F10] Coagulation factor X (EC 3.4.21.6) (Stuart factor) [Cleaved into: Factor X light chain; Factor X heavy chain; Activated factor Xa heavy chain]
[F10 FX] Coagulation factor X (EC 3.4.21.6) (Stuart factor) (Virus-activating protease) (VAP) [Cleaved into: Factor X light chain; Factor X heavy chain; Activated factor Xa heavy chain]
[Rack1 Gnb2-rs1 Gnb2l1] Receptor of activated protein C kinase 1 (12-3) (Guanine nucleotide-binding protein subunit beta-2-like 1) (Receptor for activated C kinase) (Receptor of activated protein kinase C 1) (p205) [Cleaved into: Receptor of activated protein C kinase 1, N-terminally processed (Guanine nucleotide-binding protein subunit beta-2-like 1, N-terminally processed)]
[TGFBR1 ALK5 SKR4] TGF-beta receptor type-1 (TGFR-1) (EC 2.7.11.30) (Activin A receptor type II-like protein kinase of 53kD) (Activin receptor-like kinase 5) (ALK-5) (ALK5) (Serine/threonine-protein kinase receptor R4) (SKR4) (TGF-beta type I receptor) (Transforming growth factor-beta receptor type I) (TGF-beta receptor type I) (TbetaR-I)
[F5] Coagulation factor V (Activated protein C cofactor) (Proaccelerin, labile factor) [Cleaved into: Coagulation factor V heavy chain; Coagulation factor V light chain]
[Met] Hepatocyte growth factor receptor (HGF receptor) (EC 2.7.10.1) (HGF/SF receptor) (Proto-oncogene c-Met) (Scatter factor receptor) (SF receptor) (Tyrosine-protein kinase Met)
[Tlr4 Lps] Toll-like receptor 4 (EC 3.2.2.6) (CD antigen CD284)
[FLT4 VEGFR3] Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4)
[Or22a AN11 DOR22A.1 dor53 Or22A.1 CG12193] Odorant receptor 22a
[Flt4 Flt-4 Vegfr3] Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4)
[Flt4 Flt-4 Vegfr3] Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4)
[Or22b AN12 DOR22A.2 dor67 Or22A.2 CG4231] Odorant receptor 22b
[F7 Cf7] Coagulation factor VII (EC 3.4.21.21) (Serum prothrombin conversion accelerator) [Cleaved into: Factor VII light chain; Factor VII heavy chain]
[F7] Coagulation factor VII (EC 3.4.21.21) (Serum prothrombin conversion accelerator) [Cleaved into: Factor VII light chain; Factor VII heavy chain]
[1a] Replicase polyprotein 1a (pp1a) (ORF1a polyprotein) [Cleaved into: Non-structural protein 1 (nsp1) (Leader protein); Non-structural protein 2 (nsp2) (p65 homolog); Non-structural protein 3 (nsp3) (EC 3.4.19.12) (EC 3.4.22.69) (PL2-PRO) (Papain-like proteinase) (PL-PRO); Non-structural protein 4 (nsp4); 3C-like proteinase (3CL-PRO) (3CLp) (EC 3.4.22.-) (nsp5); Non-structural protein 6 (nsp6); Non-structural protein 7 (nsp7); Non-structural protein 8 (nsp8); Non-structural protein 9 (nsp9); Non-structural protein 10 (nsp10) (Growth factor-like peptide) (GFL); Non-structural protein 11 (nsp11)]
[RACK1 GNB2L1 HLC7 PIG21] Receptor of activated protein C kinase 1 (Cell proliferation-inducing gene 21 protein) (Guanine nucleotide-binding protein subunit beta-2-like 1) (Guanine nucleotide-binding protein subunit beta-like protein 12.3) (Human lung cancer oncogene 7 protein) (HLC-7) (Receptor for activated C kinase) (Small ribosomal subunit protein RACK1) [Cleaved into: Receptor of activated protein C kinase 1, N-terminally processed (Guanine nucleotide-binding protein subunit beta-2-like 1, N-terminally processed)]
[CXCR4] C-X-C chemokine receptor type 4 (CXC-R4) (CXCR-4) (FB22) (Fusin) (HM89) (LCR1) (Leukocyte-derived seven transmembrane domain receptor) (LESTR) (Lipopolysaccharide-associated protein 3) (LAP-3) (LPS-associated protein 3) (NPYRL) (Stromal cell-derived factor 1 receptor) (SDF-1 receptor) (CD antigen CD184)

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