Abstract
The visual/β-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.
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Acknowledgements
Supported by National Institutes of Health Grants R01 DK055524 (LML), R01 GM095497 (LML), Department of Veterans Affairs Merit Review Grant I01 BX003188 (LML), and the Research Service of the Charleston, SC Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.
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Hoffmann, C., Lohse, M.J., Luttrell, L.M. (2017). Is Signaling Specificity Encoded in Arrestin Conformation?. In: Gurevich, V. (eds) The Structural Basis of Arrestin Functions. Springer, Cham. https://doi.org/10.1007/978-3-319-57553-7_17
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