PAR4_HUMAN
ID PAR4_HUMAN Reviewed; 385 AA.
AC Q96RI0; O76067; Q6DK42;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Proteinase-activated receptor 4;
DE Short=PAR-4;
DE AltName: Full=Coagulation factor II receptor-like 3;
DE AltName: Full=Thrombin receptor-like 3;
DE Flags: Precursor;
GN Name=F2RL3; Synonyms=PAR4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-120.
RX PubMed=9722561; DOI=10.1074/jbc.273.36.23290;
RA Kahn M.L., Hammes S.R., Botka C., Coughlin S.R.;
RT "Gene and locus structure and chromosomal localization of the protease-
RT activated receptor gene family.";
RL J. Biol. Chem. 273:23290-23296(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-120.
RX PubMed=9716134; DOI=10.1038/29325;
RA Kahn M.L., Zheng Y.-W., Huang W., Bigornia V., Zeng D., Moff S.,
RA Farese R.V. Jr., Tam C., Coughlin S.R.;
RT "A dual thrombin receptor system for platelet activation.";
RL Nature 394:690-694(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF ARG-47 AND ARG-68, AND VARIANT
RP THR-120.
RC TISSUE=Lymphoma;
RX PubMed=9618465; DOI=10.1073/pnas.95.12.6642;
RA Xu W.-F., Andersen H., Whitmore T.E., Presnell S.R., Yee D.P., Ching A.,
RA Gilbert T., Davie E.W., Foster D.C.;
RT "Cloning and characterization of human protease-activated receptor 4.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:6642-6646(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RA King M.M., Aronstam R.S., Sharma S.V.;
RT "cDNA clones of human proteins involved in signal transduction sequenced by
RT the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-296 AND LEU-310.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION.
RX PubMed=10079109; DOI=10.1172/jci6042;
RA Kahn M.L., Nakanishi-Matsui M., Shapiro M.J., Ishihara H., Coughlin S.R.;
RT "Protease-activated receptors 1 and 4 mediate activation of human platelets
RT by thrombin.";
RL J. Clin. Invest. 103:879-887(1999).
CC -!- FUNCTION: Receptor for activated thrombin or trypsin coupled to G
CC proteins that stimulate phosphoinositide hydrolysis. May play a role in
CC platelets activation. {ECO:0000269|PubMed:10079109}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in lung,
CC pancreas, thyroid, testis and small intestine. Not expressed in brain,
CC kidney, spinal cord and peripheral blood leukocytes. Also detected in
CC platelets.
CC -!- PTM: A proteolytic cleavage generates a new N-terminus that functions
CC as a tethered ligand.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/f2rl3/";
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DR EMBL; AF080214; AAC28860.1; -; mRNA.
DR EMBL; AF055917; AAC25699.1; -; mRNA.
DR EMBL; AY431102; AAR08487.1; -; mRNA.
DR EMBL; AF384819; AAK61908.1; -; Genomic_DNA.
DR EMBL; BC074782; AAH74782.2; -; mRNA.
DR CCDS; CCDS12350.1; -.
DR RefSeq; NP_003941.2; NM_003950.3.
DR PDB; 2ZPK; X-ray; 1.80 A; P/Q=46-53.
DR PDB; 3QDZ; X-ray; 2.80 A; E/F=39-47.
DR PDBsum; 2ZPK; -.
DR PDBsum; 3QDZ; -.
DR AlphaFoldDB; Q96RI0; -.
DR SMR; Q96RI0; -.
DR BioGRID; 114481; 3.
DR ELM; Q96RI0; -.
DR STRING; 9606.ENSP00000248076; -.
DR BindingDB; Q96RI0; -.
DR ChEMBL; CHEMBL4691; -.
DR DrugBank; DB11300; Thrombin.
DR GuidetoPHARMACOLOGY; 350; -.
DR GlyGen; Q96RI0; 1 site.
DR iPTMnet; Q96RI0; -.
DR PhosphoSitePlus; Q96RI0; -.
DR BioMuta; F2RL3; -.
DR DMDM; 116242700; -.
DR jPOST; Q96RI0; -.
DR MassIVE; Q96RI0; -.
DR PaxDb; Q96RI0; -.
DR PeptideAtlas; Q96RI0; -.
DR PRIDE; Q96RI0; -.
DR ProteomicsDB; 77962; -.
DR ABCD; Q96RI0; 2 sequenced antibodies.
DR Antibodypedia; 14245; 403 antibodies from 33 providers.
DR DNASU; 9002; -.
DR Ensembl; ENST00000248076.4; ENSP00000248076.2; ENSG00000127533.4.
DR GeneID; 9002; -.
DR KEGG; hsa:9002; -.
DR MANE-Select; ENST00000248076.4; ENSP00000248076.2; NM_003950.4; NP_003941.2.
DR UCSC; uc002nfa.4; human.
DR CTD; 9002; -.
DR DisGeNET; 9002; -.
DR GeneCards; F2RL3; -.
DR HGNC; HGNC:3540; F2RL3.
DR HPA; ENSG00000127533; Tissue enhanced (adipose tissue, lung, thyroid gland).
DR MIM; 602779; gene.
DR neXtProt; NX_Q96RI0; -.
DR OpenTargets; ENSG00000127533; -.
DR PharmGKB; PA27949; -.
DR VEuPathDB; HostDB:ENSG00000127533; -.
DR eggNOG; ENOG502QU4Y; Eukaryota.
DR GeneTree; ENSGT01050000244840; -.
DR HOGENOM; CLU_009579_8_2_1; -.
DR InParanoid; Q96RI0; -.
DR OMA; CPRAIPG; -.
DR OrthoDB; 995441at2759; -.
DR PhylomeDB; Q96RI0; -.
DR TreeFam; TF350010; -.
DR PathwayCommons; Q96RI0; -.
DR Reactome; R-HSA-375276; Peptide ligand-binding receptors.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR Reactome; R-HSA-456926; Thrombin signalling through proteinase activated receptors (PARs).
DR SignaLink; Q96RI0; -.
DR SIGNOR; Q96RI0; -.
DR BioGRID-ORCS; 9002; 8 hits in 1074 CRISPR screens.
DR EvolutionaryTrace; Q96RI0; -.
DR GeneWiki; F2RL3; -.
DR GenomeRNAi; 9002; -.
DR Pharos; Q96RI0; Tchem.
DR PRO; PR:Q96RI0; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q96RI0; protein.
DR Bgee; ENSG00000127533; Expressed in right lung and 92 other tissues.
DR ExpressionAtlas; Q96RI0; baseline and differential.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0015057; F:thrombin-activated receptor activity; TAS:ProtInc.
DR GO; GO:0007596; P:blood coagulation; TAS:ProtInc.
DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; IDA:UniProtKB.
DR GO; GO:0060155; P:platelet dense granule organization; IC:BHF-UCL.
DR GO; GO:0051482; P:positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway; IBA:GO_Central.
DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:BHF-UCL.
DR GO; GO:0035025; P:positive regulation of Rho protein signal transduction; IBA:GO_Central.
DR GO; GO:0009611; P:response to wounding; TAS:ProtInc.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR003944; Prot_act_rcpt_4.
DR InterPro; IPR003912; Protea_act_rcpt.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01428; PROTEASEAR.
DR PRINTS; PR01430; PROTEASEAR4.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Cell membrane; Disulfide bond;
KW G-protein coupled receptor; Glycoprotein; Hemostasis; Membrane; Receptor;
KW Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT PROPEP 18..47
FT /note="Removed for receptor activation"
FT /evidence="ECO:0000250"
FT /id="PRO_0000012762"
FT CHAIN 48..385
FT /note="Proteinase-activated receptor 4"
FT /id="PRO_0000012763"
FT TOPO_DOM 48..82
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 83..103
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 104..108
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 109..129
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 130..151
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 152..172
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 173..192
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 193..213
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 214..247
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 248..268
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 269..283
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 284..304
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 305..319
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 320..343
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 344..385
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 21..42
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 362..385
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 21..38
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 47..48
FT /note="Cleavage; by thrombin or trypsin"
FT /evidence="ECO:0000250"
FT CARBOHYD 56
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 149..228
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VARIANT 120
FT /note="A -> T (in dbSNP:rs773902)"
FT /evidence="ECO:0000269|PubMed:9618465,
FT ECO:0000269|PubMed:9716134, ECO:0000269|PubMed:9722561"
FT /id="VAR_028300"
FT VARIANT 215
FT /note="R -> Q (in dbSNP:rs2230799)"
FT /id="VAR_028301"
FT VARIANT 296
FT /note="F -> V (in dbSNP:rs2227346)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_012852"
FT VARIANT 310
FT /note="P -> L (in dbSNP:rs2227376)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_012853"
FT MUTAGEN 47
FT /note="R->A: No proteolytic cleavage (by thrombin or
FT trypsin)."
FT /evidence="ECO:0000269|PubMed:9618465"
FT MUTAGEN 68
FT /note="R->A: No effect on receptor activation."
FT /evidence="ECO:0000269|PubMed:9618465"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:3QDZ"
SQ 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
