Protease-activated receptor 2

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses, obesity,[1] metabolism,[2] and acts as a sensor for proteolytic enzymes generated during infection.[3]

Gene

The F2RL1 gene contains two exons and is widely expressed in human tissues. The predicted protein sequence is 83% identical to the mouse receptor sequence.[4]

Mechanism of activation

PAR2 is a member of the large family of 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins. PAR2 is also a member of the protease-activated receptor family. It is activated by trypsin, but not by thrombin. It is activated by proteolytic cleavage of its extracellular amino terminus. The new amino terminus functions as a tethered ligand and activates the receptor. Additionally, these receptors can be activated by exogenous proteases, such as house dust mite protein Der P9.[5] These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand.[6]

Agonists and antagonists

Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.[7][8][9]

Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling.[10] Synthetic small ligands also modulate biased signalling leading to different functional responses.[11]

So far, PAR2 has been co-crystallized with two different antagonist ligands,[12] while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through mutagenesis and structure-based drug design.[13]

See also

References

  1. ↑ Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP (December 2013). "Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism". FASEB Journal. 27 (12): 4757–67. doi:10.1096/fj.13-232702. PMID 23964081.
  2. ↑ Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F (October 2011). "Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation". Nature Medicine. 17 (11): 1490–7. doi:10.1038/nm.2461. PMC 3210891. PMID 22019885.
  3. ↑ Lee SE, Jeong SK, Lee SH (November 2010). "Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis". Yonsei Medical Journal. 51 (6): 808–22. doi:10.3349/ymj.2010.51.6.808. PMC 2995962. PMID 20879045.
  4. ↑ "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1".
  5. ↑ Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S (July 2001). "Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells". Journal of Immunology. 167 (2): 1014–21. doi:10.4049/jimmunol.167.2.1014. PMID 11441110.
  6. ↑ Kawabata A, Kanke T, Yonezawa D, Ishiki T, Saka M, Kabeya M, Sekiguchi F, Kubo S, Kuroda R, Iwaki M, Katsura K, Plevin R (June 2004). "Potent and metabolically stable agonists for protease-activated receptor-2: evaluation of activity in multiple assay systems in vitro and in vivo". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 1098–107. doi:10.1124/jpet.103.061010. PMID 14976227.
  7. ↑ Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES (December 2008). "Identification and characterization of novel small-molecule protease-activated receptor 2 agonists". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 799–808. doi:10.1124/jpet.108.142570. PMID 18768780.
  8. ↑ Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (October 2010). "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry. 53 (20): 7428–40. doi:10.1021/jm100984y. PMID 20873792.
  9. ↑ Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, Fairlie DP (December 2016). "PAR2 Modulators Derived from GB88". ACS Medicinal Chemistry Letters. 7 (12): 1179–1184. doi:10.1021/acsmedchemlett.6b00306. PMC 5150695. PMID 27994760.
  10. ↑ Zhao P, Metcalf M, Bunnett NW (2014). "Biased signaling of protease-activated receptors". Frontiers in Endocrinology. 5: 67. doi:10.3389/fendo.2014.00067. PMC 4026716. PMID 24860547.
  11. ↑ Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, Fairlie DP (May 2017). "Biased Signaling by Agonists of Protease Activated Receptor 2". ACS Chemical Biology. 12 (5): 1217–1226. doi:10.1021/acschembio.6b01088. PMID 28169521.
  12. ↑ Cheng RK, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (May 2017). "Structural insight into allosteric modulation of protease-activated receptor 2". Nature. 545 (7652): 112–115. doi:10.1038/nature22309. PMID 28445455.
  13. ↑ Kennedy AJ, Ballante F, Johansson JR, Milligan G, Sundström L, Nordqvist A, Carlsson J (2018-10-16). "Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling". ACS Pharmacology & Translational Science. doi:10.1021/acsptsci.8b00019.

Further reading

External links

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

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