Understanding the differential selectivity of arrestins toward the phosphorylation state of the receptor

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dc.authorid0000-0001-5950-3436
dc.contributor.authorŞensoy, Özge
dc.contributor.authorMoreira, Irina Sousa
dc.contributor.authorMorra, Giulia
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:36:53Z
dc.date.available10.07.201910:49:14
dc.date.available2019-07-10T19:36:53Z
dc.date.issued2016
dc.departmentİstanbul Medipol Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Bilgisayar Mühendisliği Bölümü
dc.description.abstractProteins in the arrestin family exhibit a conserved structural fold that nevertheless allows for significant differences in their selectivity for G-protein coupled receptors (GPCRs) and their phosphorylation states. To reveal the mechanism of activation that prepares arrestin for selective interaction with GPCRs, and to understand the basis for these differences, we used unbiased molecular dynamics simulations to compare the structural and dynamic properties of wild type Arr1 (Arr1-WT), Arr3 (Arr3-WT), and a constitutively active Arr1 mutant, Arr1-R175E, characterized by a perturbation of the phosphate recognition region called "polar core". We find that in our simulations the mutant evolves toward a conformation that resembles the known preactivated structures of an Arr1 splice-variant, and the structurally similar phosphopeptide-bound Arr2-WT, while this does not happen for Arr1-WT. Hence, we propose an activation allosteric mechanism connecting the perturbation of the polar core to a global conformational change, including the relative reorientation of N- and C-domains, and the emergence of electrostatic properties of putative binding surfaces. The underlying local structural changes are interpreted as markers of the evolution of an arrestin structure toward an active-like conformation. Similar activation related changes occur in Arr3-WT in the absence of any perturbation of the polar core, suggesting that this system could spontaneously visit preactivated states in solution. This hypothesis is proposed to explain the lower selectivity of Arr3 toward nonphosphorylated receptors. Moreover, by elucidating the allosteric mechanism underlying activation, we identify functionally critical regions on arrestin structure that can be targeted with drugs or chemical tools for functional modulation.
dc.description.sponsorshipMSCA-IF-2015, MEMBRANEPROT 659826 IF/00578/2014 UID/NEU/04539/2013 Federación Española de Enfermedades Rarasen_US
dc.identifier.citationŞensoy, Ö., Moreira, I. S. ve Morra, G. (2016). Understanding the differential selectivity of arrestins toward the phosphorylation state of the receptor. ACS Chemical Neuroscience, 7(9), 1212-1224. https://dx.doi.org/10.1021/acschemneuro.6b00073
dc.identifier.doi10.1021/acschemneuro.6b00073
dc.identifier.endpage1224
dc.identifier.issn1948-7193
dc.identifier.issue9
dc.identifier.scopusqualityQ1
dc.identifier.startpage1212
dc.identifier.urihttps://hdl.handle.net/20.500.12511/1277
dc.identifier.urihttps://dx.doi.org/10.1021/acschemneuro.6b00073
dc.identifier.volume7
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.ispartofACS Chemical Neuroscienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectarrestin Preactivated State
dc.subjectArrestin/GPCR Coupling
dc.subjectFunctional Selectivity
dc.subjectMolecular Dynamics Simulations
dc.titleUnderstanding the differential selectivity of arrestins toward the phosphorylation state of the receptor
dc.typeArticle

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