Understanding the Differential Selectivity of Arrestins toward the Phosphorylation State of the Receptor
| Autor: | Ozge Sensoy, Irina S. Moreira, Giulia Morra |
|---|---|
| Přispěvatelé: | Sub NMR Spectroscopy, NMR Spectroscopy |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Rotation Physiology Arrestins Protein Conformation Cognitive Neuroscience Allosteric regulation Molecular Conformation arrestin preactivated state Biology Biochemistry Receptors G-Protein-Coupled 03 medical and health sciences Protein structure Functional selectivity Arrestin Animals Humans Computer Simulation Phosphorylation G protein-coupled receptor Wild type Cell Biology General Medicine molecular dynamics simulations Cell biology 030104 developmental biology Arrestin/GPCR coupling Amino Acid Substitution Nonlinear Dynamics Mutation Arrestin beta 1 functional selectivity Protein Binding |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP ACS chemical neuroscience 7 (2016): 1212–1224. doi:10.1021/acschemneuro.6b00073 info:cnr-pdr/source/autori:Sensoy O.; Moreira I.S.; Morra G./titolo:Understanding the Differential Selectivity of Arrestins toward the Phosphorylation State of the Receptor/doi:10.1021%2Facschemneuro.6b00073/rivista:ACS chemical neuroscience/anno:2016/pagina_da:1212/pagina_a:1224/intervallo_pagine:1212–1224/volume:7 ACS Chemical Neuroscience ACS Chemical Neuroscience, 7(9), 1212. American Chemical Society |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.6b00073 |
| Popis: | Proteins 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. MSCA-IF-2015, MEMBRANEPROT 659826 IF/00578/2014 UID/NEU/04539/2013 Federación Española de Enfermedades Raras |
| Databáze: | OpenAIRE |
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