Coagulation factor II receptor

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PDB 1nrn EBI.jpg
Available structures
PDBOrtholog search: PDBe RCSB
AliasesF2R, CHTR, PAR-1, PAR1, TR, Coagulation factor II receptor, coagulation factor II thrombin receptor
External IDsOMIM: 187930 MGI: 101802 HomoloGene: 1510 GeneCards: F2R
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 5: 76.72 – 76.74 MbChr 13: 95.74 – 95.75 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Proteinase-activated receptor 1 (PAR1) also known as protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene.[5] 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.[6] It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.[7]


PAR1 is a transmembrane G-protein-coupled receptor (GPCR) that shares much of its structure with the other protease-activated receptors.[8][9] These characteristics include having seven transmembrane alpha helices, four extracellular loops and three intracellular loops.[9] 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.[8]

Signal transduction pathway[edit]

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.


PAR1 is activated when the terminal 41 amino acids of its N-terminus are cleaved by thrombin, a serine protease.[10] 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.[11] This proteolytic cleavage is irreversible and the loose peptide, often referred to as parstatin, is then released outside of the cell.[10] 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.[12]


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 G12/13 which in turn activates Rho and Rho kinase.[8] 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.[8] Coupling can also occur with Gq, leading to phospholipase C-β activation; this pathway results in the stimulation of protein kinase C (PKC) which impacts platelet activation.[8]

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.[8] This also activates protein kinase C which stimulates platelet aggregation and therefore blood coagulation further down the pathway.[11]


The phosphorylation of PAR1's cytoplasmic tail and subsequent binding to arrestin uncouples the protein from G protein signaling.[10][11] 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.[11] This internalization and degradation process is necessary for the termination of receptor signaling.[10]

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.[13] 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.[14]

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.



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.[15] So, even in the absence of thrombin, SFLLRN binding can garner a response from cleaved or uncleaved PAR1.[16]


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

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000181104 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048376 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Bahou WF, Nierman WC, Durkin AS, Potter CL, Demetrick DJ (September 1993). "Chromosomal assignment of the human thrombin receptor gene: localization to region q13 of chromosome 5". Blood. 82 (5): 1532–7. doi:10.1182/blood.V82.5.1532.1532. PMID 8395910.
  6. ^ "José RJ, Williams AE, Chambers RC (February 2014). "Proteinase-activated receptors in fibroproliferative lung disease". Thorax. 69 (2): 190–2. doi:10.1136/thoraxjnl-2013-204367. PMID 24186921.
  7. ^ Feistritzer C, Riewald M (April 2005). "Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation". Blood. 105 (8): 3178–84. doi:10.1182/blood-2004-10-3985. PMID 15626732. S2CID 24170814.
  8. ^ a b c d e f Michelson AD (2013). Platelets (3rd ed.). Amsterdam: Elsevier. ISBN 9780123878380. OCLC 820818942.
  9. ^ a b Spoerri PM, Kato HE, Pfreundschuh M, Mari SA, Serdiuk T, Thoma J, et al. (June 2018). "Structural Properties of the Human Protease-Activated Receptor 1 Changing by a Strong Antagonist". Structure. 26 (6): 829–838.e4. doi:10.1016/j.str.2018.03.020. PMID 29731231.
  10. ^ a b c d Soh UJ, Dores MR, Chen B, Trejo J (May 2010). "Signal transduction by protease-activated receptors". British Journal of Pharmacology. 160 (2): 191–203. doi:10.1111/j.1476-5381.2010.00705.x. PMC 2874842. PMID 20423334.
  11. ^ a b c d Arora P, Ricks TK, Trejo J (March 2007). "Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer". Journal of Cell Science. 120 (Pt 6): 921–8. doi:10.1242/jcs.03409. PMID 17344429.
  12. ^ Pfreundschuh M, Alsteens D, Wieneke R, Zhang C, Coughlin SR, Tampé R, et al. (November 2015). "Identifying and quantifying two ligand-binding sites while imaging native human membrane receptors by AFM". Nature Communications. 6 (1): 8857. doi:10.1038/ncomms9857. PMC 4660198. PMID 26561004.
  13. ^ Chen B, Siderovski DP, Neubig RR, Lawson MA, Trejo J (January 2014). "Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins". The Journal of Biological Chemistry. 289 (3): 1580–91. doi:10.1074/jbc.m113.528273. PMC 3894338. PMID 24297163.
  14. ^ Paing MM, Johnston CA, Siderovski DP, Trejo J (April 2006). "Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization". Molecular and Cellular Biology. 26 (8): 3231–42. doi:10.1128/MCB.26.8.3231-3242.2006. PMC 1446942. PMID 16581796.
  15. ^ a b Zhang C, Srinivasan Y, Arlow DH, Fung JJ, Palmer D, Zheng Y, et al. (December 2012). "High-resolution crystal structure of human protease-activated receptor 1". Nature. 492 (7429): 387–92. doi:10.1038/nature11701. PMC 3531875. PMID 23222541.
  16. ^ Hammes SR, Coughlin SR (February 1999). "Protease-activated receptor-1 can mediate responses to SFLLRN in thrombin-desensitized cells: evidence for a novel mechanism for preventing or terminating signaling by PAR1's tethered ligand". Biochemistry. 38 (8): 2486–93. doi:10.1021/bi982527i. PMID 10029543.
  17. ^ Gryka RJ, Buckley LF, Anderson SM (March 2017). "Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease". Drugs in R&D. 17 (1): 65–72. doi:10.1007/s40268-016-0158-4. PMC 5318326. PMID 28063023.
  18. ^ José RJ, Williams AE, Mercer PF, Sulikowski MG, Brown JS, Chambers RC (June 2015). "Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection". Journal of Immunology. 194 (12): 6024–34. doi:10.4049/jimmunol.1500124. PMC 4456635. PMID 25948816.

Further reading[edit]

External links[edit]

  • 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.