Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors

Prokop, S., Perry, N. A., Vishnivetskiy, S. A., Toth, A. D., Inoue, A., Milligan, G. , Iverson, T. M., Hunyady, L. and Gurevich, V. V. (2017) Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors. Cellular Signalling, 36, pp. 98-107. (doi: 10.1016/j.cellsig.2017.04.021) (PMID:28461104)

Abstract

Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central “crest” of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M2 muscarinic receptor, so that agonist activation of the M2 did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M2, whereas its interactions with other receptors, including the β2-adrenergic receptor and the D1 and D2 dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β2-adrenergic and D2 dopamine receptors, while reducing its interaction with the D1 dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Milligan, Professor Graeme
• Authors: Prokop, S., Perry, N. A., Vishnivetskiy, S. A., Toth, A. D., Inoue, A., Milligan, G., Iverson, T. M., Hunyady, L., and Gurevich, V. V.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Cellular Signalling
• Publisher: Elsevier
• ISSN: 0898-6568
• ISSN (Online): 1873-3913
• Published Online: 28 April 2017
• Copyright Holders: Copyright © 2017 Elsevier
• First Published: First published in Cellular Signalling 36:98-107
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher