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

Prokop S, Perry NA, Vishnivetskiy SA, Toth AD, Inoue A, Milligan G, Iverson TM, Hunyady L, Gurevich VV
Cell Signal. 2017 36: 98-107

PMID: 28461104 · PMCID: PMC5797668 · DOI:10.1016/j.cellsig.2017.04.021

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 M muscarinic receptor, so that agonist activation of the M did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M, whereas its interactions with other receptors, including the β-adrenergic receptor and the D and D dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β-adrenergic and D dopamine receptors, while reducing its interaction with the D 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.

Copyright © 2017. Published by Elsevier Inc.

MeSH Terms (16)

Amino Acid Sequence Animals Arrestins Cattle Chlorocebus aethiops Conserved Sequence COS Cells HEK293 Cells Humans Lysine Mutant Proteins Mutation Protein Binding Protein Structure, Secondary Receptors, G-Protein-Coupled Rhodopsin

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