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ACS Chem Neurosci. 2016 Sep 21;7(9):1212-24. doi: 10.1021/acschemneuro.6b00073. Epub 2016 Jul 22.

Understanding the Differential Selectivity of Arrestins toward the Phosphorylation State of the Receptor.

Author information

1
The School of Engineering and Natural Sciences, Istanbul Medipol University , 34810 Istanbul, Turkey.
2
Department of Physiology and Biophysics, Weill Cornell Medical College , 1300 York Ave, New York, New York 10065, United States.
3
CNC - Center for Neuroscience and Cell Biology; Rua Larga, FMUC, Polo I, 1┬░andar, Universidade de Coimbra , 3004-517 Coimbra, Portugal.
4
Bijvoet Center for Biomolecular Research, Faculty of Science - Chemistry, Utrecht University , Utrecht 3584CH, The Netherlands.
5
ICRM-CNR Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche , Via Mario Bianco 9, 20131 Milano, Italia.

Abstract

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.

KEYWORDS:

Arrestin/GPCR coupling; arrestin preactivated state; functional selectivity; molecular dynamics simulations

PMID:
27405242
DOI:
10.1021/acschemneuro.6b00073
[Indexed for MEDLINE]

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