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Is signaling specificity encoded in arrestin conformation?

Item Type:Book Section
Title:Is signaling specificity encoded in arrestin conformation?
Creators Name:Hoffmann, C., Lohse, M.J. and Luttrell, L.M.
Abstract:The visual/{beta}-arrestins perform remarkably diverse roles in cells. Possessing the capacity to detect and bind hundreds of different activated GPCRs, they are integral to the control of GPCR desensitization, internalization and intracellular trafficking. At the same time, they are able to bind and localize dozens of cargo proteins, including signaling pathway intermediates that affect the tonic level of pathway activity and in some cases confer GPCR-dependent regulation. A fundamental question in biology is how proteins like arrestins can achieve the conformational flexibility necessary to interact with so many different partners while maintaining the specificity necessary for fidelity in signal transduction. Recent data, both from static structures of arrestins in their basal and ‘activated’ conformations, and dynamic resonance energy transfer measurements, have begun to provide answers. Crystallographic and mutagenesis data indicate that the conformational shifts occurring upon receptor engagement are determined by contact between the arrestin globular domains and a relatively few residues within the GPCR intracellular loops. These contacts, in turn, impose receptor-specific arrestin conformations that influence the avidity with which it binds the receptor and its ability to engage certain downstream partners. Differences in ligand structure are likewise encoded in receptor conformation and transmitted to the arrestin, providing the physical basis for ligand ‘bias’. Resonance energy transfer data also indicate that arrestins maintain their ‘active’ conformation for a period of time after letting go of the receptor, raising the possibility that arrestins, like heterotrimeric G proteins, might be activated catalytically.
Keywords:Arrestin, GPCR, Ligand Bias, Signal Transduction, Conformational Change
Title of Book:The Structural Basis of Arrestin Functions
ISBN:978-3-319-57552-0
Publisher:Springer
Page Range:235-253
Date:25 May 2017
Official Publication:https://doi.org/10.1007/978-3-319-57553-7_17

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