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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