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

Susanne Prokop, Nicole A. Perry, Sergey A. Vishnivetskiy, Andras D. Toth, Asuka Inoue, Graeme Milligan, Tina M. Iverson, Laszlo Hunyady, Vsevolod V. Gurevich

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11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)98-107
Number of pages10
JournalCellular Signalling
Volume36
DOIs
Publication statusPublished - 2017 Aug 1

Keywords

  • Arrestin
  • GPCRs
  • Protein engineering
  • Protein-protein interactions
  • Receptor specificity

ASJC Scopus subject areas

  • Cell Biology

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