Proteinase-activated receptor 1

"F2R" redirects here. For the Navy fighter, see Ryan XF2R Dark Shark.

Proteinase-activated receptor 1 (PAR1) also known as protease-activated receptor 1, coagulation factor II receptor and thrombin receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

F2R
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1NRN, 1NRO, 1NRP, 1NRQ, 1NRR, 3BEF, 3HKI, 3HKJ, 3LU9, 3VW7
Identifiers
Aliases	F2R, CHTR, PAR-1, PAR1, TR, Coagulation factor II receptor, coagulation factor II thrombin receptor
External IDs	OMIM: 187930; MGI: 101802; HomoloGene: 1510; GeneCards: F2R; OMA:F2R - orthologs
Gene location (Human) Chr. Chromosome 5 (human) Band 5q13.3 Start 76,716,126 bp End 76,735,770 bp
Gene location (Mouse) Chr. Chromosome 13 (mouse) Band 13 D1|13 50.21 cM Start 95,738,311 bp End 95,754,995 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium ventricular zone decidua ganglionic eminence right lung gallbladder skin of hip right coronary artery lower lobe of lung Descending thoracic aorta Top expressed in molar gastrula renal corpuscle endothelial cell of lymphatic vessel epithelium of lens external carotid artery internal carotid artery ciliary body decidua conjunctival fornix More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity thrombin-activated receptor activity G-protein beta-subunit binding protein binding G-protein alpha-subunit binding signaling receptor binding Cellular component integral component of membrane platelet dense tubular network late endosome Golgi apparatus postsynaptic membrane membrane neuromuscular junction plasma membrane integral component of plasma membrane extracellular region cell surface early endosome caveola Biological process negative regulation of neuron apoptotic process positive regulation of collagen biosynthetic process hemostasis establishment of synaptic specificity at neuromuscular junction release of sequestered calcium ion into cytosol platelet dense granule organization regulation of sensory perception of pain thrombin-activated receptor signaling pathway positive regulation of cell migration positive regulation of cytosolic calcium ion concentration anatomical structure morphogenesis blood coagulation positive regulation of release of sequestered calcium ion into cytosol platelet activation phospholipase C-activating G protein-coupled receptor signaling pathway positive regulation of cysteine-type endopeptidase activity involved in apoptotic process response to lipopolysaccharide positive regulation of transcription, DNA-templated protein kinase C-activating G protein-coupled receptor signaling pathway positive regulation of blood coagulation response to wounding positive regulation of vasoconstriction positive regulation of cell population proliferation connective tissue replacement involved in inflammatory response wound healing positive regulation of ERK1 and ERK2 cascade regulation of interleukin-1 beta production positive regulation of I-kappaB kinase/NF-kappaB signaling homeostasis of number of cells within a tissue positive regulation of phosphatidylinositol 3-kinase signaling regulation of blood coagulation inflammatory response negative regulation of glomerular filtration activation of cysteine-type endopeptidase activity involved in apoptotic process positive regulation of smooth muscle contraction positive regulation of MAPK cascade negative regulation of cell population proliferation negative regulation of renin secretion into blood stream signal transduction positive regulation of calcium ion transport positive regulation of Rho protein signal transduction positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway trans-synaptic signaling by endocannabinoid, modulating synaptic transmission positive regulation of GTPase activity cell-cell junction maintenance G protein-coupled receptor signaling pathway positive regulation of receptor signaling pathway via JAK-STAT Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2149 14062 Ensembl ENSG00000181104 ENSMUSG00000048376 UniProt P25116 P30558 RefSeq (mRNA) NM_001992 NM_001311313 NM_010169 RefSeq (protein) NP_001298242 NP_001983 NP_034299 Location (UCSC) Chr 5: 76.72 – 76.74 Mb Chr 13: 95.74 – 95.75 Mb PubMed search
Wikidata
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Structure

PAR1 is a transmembrane G-protein-coupled receptor (GPCR) that shares much of its structure with the other protease-activated receptors. These characteristics include having seven transmembrane alpha helices, four extracellular loops and three intracellular loops. PAR1 specifically contains 425 amino acid residues arranged for optimal binding of thrombin at its extracellular N-terminus. The C-terminus of PAR1 is located on the intracellular side of the cell membrane as part of its cytoplasmic tail.

Signal transduction pathway

This image gives an overview of the cleavage of PAR1 by thrombin. Thrombin, in red, binds to the cleavage site at the extracellular N-terminus of PAR1. Thrombin cleaves the peptide bond between Arg-41 and Ser-42 to reveal a tethered ligand at the new N-terminus and the cleaved peptide, in orange, is released outside of the cell.

Activation

PAR1 is activated when the terminal 41 amino acids of its N-terminus are cleaved by thrombin, a serine protease. Thrombin recognizes PAR1 by a Lysine-Aspartate-Proline-Arginine-Serine sequence at the N-terminal, where it cuts the peptide bond between Arginine-41 and Serine-42. The affinity of thrombin to this specific cleavage site in PAR1 is further aided by secondary interactions between thrombin's exosite and an acidic region of amino acid residues located C-terminal to Ser-42. This proteolytic cleavage is irreversible and the loose peptide, often referred to as parstatin, is then released outside of the cell. The newly revealed N-terminus acts as a tethered ligand that binds to a binding region between extracellular loops 3 and 4 of PAR1, therefore activating the protein. The binding instigates conformational changes in the protein that ultimately allow for the binding of G-proteins to sites on the intracellular region of PAR1.

Signalling

Once cleaved, PAR1 can activate G-proteins that bind to several locations on its intracellular loops. For example, PAR1 in conjunction with PAR4 can couple to and activate G-protein G_12/13 which in turn activates Rho and Rho kinase. This pathway leads to the quick alteration of platelet shape due to actin contractions that lead to platelet mobility, as well as the release of granules which are both necessary for platelet aggregation. Coupling can also occur with G_q, leading to phospholipase C-β activation; this pathway results in the stimulation of protein kinase C (PKC) which impacts platelet activation.

Additionally, both PAR1 and PAR4 can couple to G-protein q which stimulates intracellular movement for Calcium ions that serve as second messengers for platelet activation. This also activates protein kinase C which stimulates platelet aggregation and therefore blood coagulation further down the pathway.

Termination

The phosphorylation of PAR1's cytoplasmic tail and subsequent binding to arrestin uncouples the protein from G protein signaling. These phosphorylated PAR1s are transported back into the cell via endosomes where they are sent to Golgi bodies. The cleaved PAR1s are then sorted and transported to lysosomes where they are degraded. This internalization and degradation process is necessary for the termination of receptor signaling.

In order to regain thrombin responsiveness, PAR1 must be replenished in the cell surface. Uncleaved PAR1 in the cell membrane gets bound by the AP2 adaptor complex at a tyrosine motif on the intracellular C-terminus, which stimulates the endocytosis of the unactivated PAR1. It is then stored in clathrin-coated vesicles within the cytosol and ultimately protected from proteolysis. This ensures that there is a constant supply of uncleaved PAR1 that can be cycled into the plasma membrane independent of PAR1 reproduction, thus resensitizing the cell to thrombin and resetting the signal transduction pathway.

This is a rendering of PAR1's structure when bound to an antagonist, Vorapaxar. The light blue structures represent the seven transmembrane alpha helices of PAR1. The green structures represent the extracellular loops and the orange structures represent the intracellular loops. The red molecule is Vorapaxar. C-terminal tail not pictured.

Ligands

Agonists

Finding selective agonists for PAR1 has also been a topic of interest for researchers. A synthetic SFLLRN peptide has been found to serve as an agonist for PAR1. The SFLLRN peptide mimics the first six residues of the N-terminal tethered ligand of activated PAR1 and binds to the same binding site on the second extracellular loop. So, even in the absence of thrombin, SFLLRN binding can garner a response from cleaved or uncleaved PAR1.

Antagonists

Selective antagonists for the PAR1 receptor have been developed for use as anti-clotting agents.

• SCH-79797
• Vorapaxar, sold under the brand name Zontivity, is a first-in-class anti-platelet drug used in the treatment of heart disease in patients with a history of heart attacks and peripheral artery disease. Vorapaxar has been recently shown to attenuate the neutrophilic inflammatory response to Streptococcus pneumoniae by reducing levels of pro-inflammatory cytokines such as IL-1β and chemokines CXCL1, CCL2 and CCL7. PAR1 is inhibited by Vorapaxar when the molecule binds to a binding pocket between extracellular loop 2 and 3 of the PAR1 where it stabilizes the inactivated protein structure and prevents the switch to the active conformation.

See also

• Protease-activated receptor

Further reading

• Coughlin SR, Vu TK, Hung DT, Wheaton VI (February 1992). "Characterization of a functional thrombin receptor. Issues and opportunities". The Journal of Clinical Investigation. 89 (2): 351–5. doi:10.1172/JCI115592. PMC 442859. PMID 1310691.
• Wu H, Zhang Z, Li Y, Zhao R, Li H, Song Y, et al. (October 2010). "Time course of upregulation of inflammatory mediators in the hemorrhagic brain in rats: correlation with brain edema". Neurochemistry International. 57 (3): 248–53. doi:10.1016/j.neuint.2010.06.002. PMC 2910823. PMID 20541575.
• Howell DC, Laurent GJ, Chambers RC (April 2002). "Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis". Biochemical Society Transactions. 30 (2): 211–6. doi:10.1042/BST0300211. PMID 12023853. S2CID 32822567.
• Tellez C, Bar-Eli M (May 2003). "Role and regulation of the thrombin receptor (PAR-1) in human melanoma". Oncogene. 22 (20): 3130–7. doi:10.1038/sj.onc.1206453. PMID 12789289.
• Remillard CV, Yuan JX (May 2005). "PGE2 and PAR-1 in pulmonary fibrosis: a case of biting the hand that feeds you?". American Journal of Physiology. Lung Cellular and Molecular Physiology. 288 (5): L789-92. doi:10.1152/ajplung.00016.2005. PMID 15821019. S2CID 172096.
• Leger AJ, Covic L, Kuliopulos A (September 2006). "Protease-activated receptors in cardiovascular diseases". Circulation. 114 (10): 1070–7. doi:10.1161/CIRCULATIONAHA.105.574830. PMID 16952995.
• Traynelis SF, Trejo J (May 2007). "Protease-activated receptor signaling: new roles and regulatory mechanisms". Current Opinion in Hematology. 14 (3): 230–5. doi:10.1097/MOH.0b013e3280dce568. PMID 17414212. S2CID 30443240.
• Vu TK, Hung DT, Wheaton VI, Coughlin SR (March 1991). "Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation". Cell. 64 (6): 1057–68. doi:10.1016/0092-8674(91)90261-V. PMID 1672265. S2CID 27467574.
• Wojtukiewicz MZ, Tang DG, Ben-Josef E, Renaud C, Walz DA, Honn KV (February 1995). "Solid tumor cells express functional "tethered ligand" thrombin receptor". Cancer Research. 55 (3): 698–704. PMID 7834643.
• Hein L, Ishii K, Coughlin SR, Kobilka BK (November 1994). "Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitization of a G protein-coupled receptor". The Journal of Biological Chemistry. 269 (44): 27719–26. doi:10.1016/S0021-9258(18)47045-7. PMID 7961693.
• Mathews II, Padmanabhan KP, Ganesh V, Tulinsky A, Ishii M, Chen J, et al. (March 1994). "Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes". Biochemistry. 33 (11): 3266–79. doi:10.1021/bi00177a018. PMID 8136362.
• Offermanns S, Laugwitz KL, Spicher K, Schultz G (January 1994). "G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 91 (2): 504–8. Bibcode:1994PNAS...91..504O. doi:10.1073/pnas.91.2.504. PMC 42977. PMID 8290554.
• Hoffman M, Church FC (August 1993). "Response of blood leukocytes to thrombin receptor peptides". Journal of Leukocyte Biology. 54 (2): 145–51. doi:10.1002/jlb.54.2.145. PMID 8395550. S2CID 9124992.
• Schmidt VA, Vitale E, Bahou WF (April 1996). "Genomic cloning and characterization of the human thrombin receptor gene. Structural similarity to the proteinase activated receptor-2 gene". The Journal of Biological Chemistry. 271 (16): 9307–12. doi:10.1074/jbc.271.16.9809. PMID 8621593.
• Li F, Baykal D, Horaist C, Yan CN, Carr BN, Rao GN, Runge MS (October 1996). "Cloning and identification of regulatory sequences of the human thrombin receptor gene". The Journal of Biological Chemistry. 271 (42): 26320–8. doi:10.1074/jbc.271.42.26320. PMID 8824285.
• Shapiro MJ, Trejo J, Zeng D, Coughlin SR (December 1996). "Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization". The Journal of Biological Chemistry. 271 (51): 32874–80. doi:10.1074/jbc.271.51.32874. PMID 8955127.
• Ogino Y, Tanaka K, Shimizu N (November 1996). "Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells". European Journal of Pharmacology. 316 (1): 105–9. doi:10.1016/S0014-2999(96)00653-X. PMID 8982657.
• Molino M, Bainton DF, Hoxie JA, Coughlin SR, Brass LF (February 1997). "Thrombin receptors on human platelets. Initial localization and subsequent redistribution during platelet activation". The Journal of Biological Chemistry. 272 (9): 6011–7. doi:10.1074/jbc.272.9.6011. PMID 9038223.
• Renesto P, Si-Tahar M, Moniatte M, Balloy V, Van Dorsselaer A, Pidard D, Chignard M (March 1997). "Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor". Blood. 89 (6): 1944–53. doi:10.1182/blood.V89.6.1944. PMID 9058715.

External links

• Overview of all the structural information available in the PDB for UniProt: P25116 (Proteinase-activated receptor 1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.