| Structural highlights
Function
C562_ECOLX Electron-transport protein of unknown function.PAR2_HUMAN Receptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as G alpha-q, G alpha-11, G alpha-14, G alpha-12 and G alpha-13, but probably not with G(o) alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to G alpha-q/11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of G alpha-q/11 and involves promotion of cofilin dephosphoryltaion and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as proinflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immnune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Publication Abstract from PubMed
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.
Structural insight into allosteric modulation of protease-activated receptor 2.,Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Dore AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundstrom L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N Nature. 2017 Apr 26. doi: 10.1038/nature22309. PMID:28445455[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, Henry PJ, Carr MJ, Hamilton JR, Moffatt JD. A protective role for protease-activated receptors in the airways. Nature. 1999 Mar 11;398(6723):156-60. PMID:10086357 doi:http://dx.doi.org/10.1038/18223
- ↑ DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol. 2000 Mar 20;148(6):1267-81. PMID:10725339
- ↑ Kanke T, Macfarlane SR, Seatter MJ, Davenport E, Paul A, McKenzie RC, Plevin R. Proteinase-activated receptor-2-mediated activation of stress-activated protein kinases and inhibitory kappa B kinases in NCTC 2544 keratinocytes. J Biol Chem. 2001 Aug 24;276(34):31657-66. Epub 2001 Jun 18. PMID:11413129 doi:http://dx.doi.org/10.1074/jbc.M100377200
- ↑ Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S. Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells. J Immunol. 2001 Jul 15;167(2):1014-21. PMID:11441110
- ↑ Lourbakos A, Potempa J, Travis J, D'Andrea MR, Andrade-Gordon P, Santulli R, Mackie EJ, Pike RN. Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect Immun. 2001 Aug;69(8):5121-30. PMID:11447194 doi:http://dx.doi.org/10.1128/IAI.69.8.5121-5130.2001
- ↑ Miike S, McWilliam AS, Kita H. Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2. J Immunol. 2001 Dec 1;167(11):6615-22. PMID:11714832
- ↑ Bolton SJ, McNulty CA, Thomas RJ, Hewitt CR, Wardlaw AJ. Expression of and functional responses to protease-activated receptors on human eosinophils. J Leukoc Biol. 2003 Jul;74(1):60-8. PMID:12832443
- ↑ Shpacovitch VM, Varga G, Strey A, Gunzer M, Mooren F, Buddenkotte J, Vergnolle N, Sommerhoff CP, Grabbe S, Gerke V, Homey B, Hollenberg M, Luger TA, Steinhoff M. Agonists of proteinase-activated receptor-2 modulate human neutrophil cytokine secretion, expression of cell adhesion molecules, and migration within 3-D collagen lattices. J Leukoc Biol. 2004 Aug;76(2):388-98. Epub 2004 May 20. PMID:15155775 doi:http://dx.doi.org/10.1189/jlb.0503221
- ↑ Feistritzer C, Lenta R, Riewald M. Protease-activated receptors-1 and -2 can mediate endothelial barrier protection: role in factor Xa signaling. J Thromb Haemost. 2005 Dec;3(12):2798-805. PMID:16359518 doi:http://dx.doi.org/10.1111/j.1538-7836.2005.01610.x
- ↑ Luo W, Wang Y, Hanck T, Stricker R, Reiser G. Jab1, a novel protease-activated receptor-2 (PAR-2)-interacting protein, is involved in PAR-2-induced activation of activator protein-1. J Biol Chem. 2006 Mar 24;281(12):7927-36. Epub 2006 Jan 12. PMID:16410250 doi:http://dx.doi.org/10.1074/jbc.M510784200
- ↑ Csernok E, Ai M, Gross WL, Wicklein D, Petersen A, Lindner B, Lamprecht P, Holle JU, Hellmich B. Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Blood. 2006 Jun 1;107(11):4440-8. Epub 2006 Feb 14. PMID:16478888 doi:http://dx.doi.org/10.1182/blood-2005-05-1875
- ↑ Winter MC, Shasby SS, Ries DR, Shasby DM. PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier: protective effect of beta-agonists. Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L628-35. Epub 2006 May 19. PMID:16714334 doi:http://dx.doi.org/10.1152/ajplung.00046.2006
- ↑ Chiu LL, Perng DW, Yu CH, Su SN, Chow LP. Mold allergen, pen C 13, induces IL-8 expression in human airway epithelial cells by activating protease-activated receptor 1 and 2. J Immunol. 2007 Apr 15;178(8):5237-44. PMID:17404307
- ↑ Zoudilova M, Kumar P, Ge L, Wang P, Bokoch GM, DeFea KA. Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J Biol Chem. 2007 Jul 13;282(28):20634-46. Epub 2007 May 11. PMID:17500066 doi:http://dx.doi.org/10.1074/jbc.M701391200
- ↑ Goon Goh F, Sloss CM, Cunningham MR, Nilsson M, Cadalbert L, Plevin R. G-protein-dependent and -independent pathways regulate proteinase-activated receptor-2 mediated p65 NFkappaB serine 536 phosphorylation in human keratinocytes. Cell Signal. 2008 Jul;20(7):1267-74. doi: 10.1016/j.cellsig.2008.02.015. Epub, 2008 Feb 29. PMID:18424071 doi:http://dx.doi.org/10.1016/j.cellsig.2008.02.015
- ↑ Feld M, Shpacovitch VM, Ehrhardt C, Kerkhoff C, Hollenberg MD, Vergnolle N, Ludwig S, Steinhoff M. Agonists of proteinase-activated receptor-2 enhance IFN-gamma-inducible effects on human monocytes: role in influenza A infection. J Immunol. 2008 May 15;180(10):6903-10. PMID:18453611
- ↑ Hong JH, Hong JY, Park B, Lee SI, Seo JT, Kim KE, Sohn MH, Shin DM. Chitinase activates protease-activated receptor-2 in human airway epithelial cells. Am J Respir Cell Mol Biol. 2008 Nov;39(5):530-5. doi: 10.1165/rcmb.2007-0410OC., Epub 2008 May 12. PMID:18474671 doi:http://dx.doi.org/10.1165/rcmb.2007-0410OC
- ↑ Rallabhandi P, Nhu QM, Toshchakov VY, Piao W, Medvedev AE, Hollenberg MD, Fasano A, Vogel SN. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem. 2008 Sep 5;283(36):24314-25. doi: 10.1074/jbc.M804800200. Epub 2008 , Jul 11. PMID:18622013 doi:http://dx.doi.org/10.1074/jbc.M804800200
- ↑ Khoufache K, LeBouder F, Morello E, Laurent F, Riffault S, Andrade-Gordon P, Boullier S, Rousset P, Vergnolle N, Riteau B. Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway. J Immunol. 2009 Jun 15;182(12):7795-802. doi: 10.4049/jimmunol.0803743. PMID:19494303 doi:http://dx.doi.org/10.4049/jimmunol.0803743
- ↑ McIntosh K, Cunningham MR, Cadalbert L, Lockhart J, Boyd G, Ferrell WR, Plevin R. Proteinase-activated receptor-2 mediated inhibition of TNFalpha-stimulated JNK activation - A novel paradigm for G(q/11) linked GPCRs. Cell Signal. 2010 Feb;22(2):265-73. doi: 10.1016/j.cellsig.2009.09.028. Epub 2009, Sep 23. PMID:19781631 doi:http://dx.doi.org/10.1016/j.cellsig.2009.09.028
- ↑ Matsuwaki Y, Wada K, White TA, Benson LM, Charlesworth MC, Checkel JL, Inoue Y, Hotta K, Ponikau JU, Lawrence CB, Kita H. Recognition of fungal protease activities induces cellular activation and eosinophil-derived neurotoxin release in human eosinophils. J Immunol. 2009 Nov 15;183(10):6708-16. doi: 10.4049/jimmunol.0901220. Epub 2009 , Oct 28. PMID:19864598 doi:http://dx.doi.org/10.4049/jimmunol.0901220
- ↑ Nhu QM, Shirey K, Teijaro JR, Farber DL, Netzel-Arnett S, Antalis TM, Fasano A, Vogel SN. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol. 2010 Jan;3(1):29-39. doi: 10.1038/mi.2009.120. Epub 2009 Oct 28. PMID:19865078 doi:http://dx.doi.org/10.1038/mi.2009.120
- ↑ Bae JS, Yang L, Rezaie AR. Factor X/Xa elicits protective signaling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1. J Biol Chem. 2010 Nov 5;285(45):34803-12. doi: 10.1074/jbc.M110.163642. Epub 2010, Sep 8. PMID:20826780 doi:http://dx.doi.org/10.1074/jbc.M110.163642
- ↑ Shpacovitch VM, Feld M, Holzinger D, Kido M, Hollenberg MD, Levi-Schaffer F, Vergnolle N, Ludwig S, Roth J, Luger T, Steinhoff M. Role of proteinase-activated receptor-2 in anti-bacterial and immunomodulatory effects of interferon-gamma on human neutrophils and monocytes. Immunology. 2011 Jul;133(3):329-39. doi: 10.1111/j.1365-2567.2011.03443.x. Epub, 2011 Apr 19. PMID:21501162 doi:http://dx.doi.org/10.1111/j.1365-2567.2011.03443.x
- ↑ Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Dore AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundstrom L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N. Structural insight into allosteric modulation of protease-activated receptor 2. Nature. 2017 Apr 26. doi: 10.1038/nature22309. PMID:28445455 doi:http://dx.doi.org/10.1038/nature22309
|
