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, L. Hunyady, Vsevolod V. Gurevich

Research output: Contribution to journalArticle

9 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 - Aug 1 2017

Fingerprint

G-Protein-Coupled Receptors
Arrestin
Mutation
Dopamine D1 Receptors
Dopamine D2 Receptors
Arrestins
Muscarinic M2 Receptors
Adrenergic Agents
Adrenergic Receptors
beta-Arrestin 2

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

Prokop, S., Perry, N. A., Vishnivetskiy, S. A., Toth, A. D., Inoue, A., Milligan, G., ... 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

Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors. / Prokop, Susanne; Perry, Nicole A.; Vishnivetskiy, Sergey A.; Toth, Andras D.; Inoue, Asuka; Milligan, Graeme; Iverson, Tina M.; Hunyady, L.; Gurevich, Vsevolod V.

In: Cellular Signalling, Vol. 36, 01.08.2017, p. 98-107.

Research output: Contribution to journalArticle

Prokop, S, Perry, NA, Vishnivetskiy, SA, Toth, AD, Inoue, A, Milligan, G, Iverson, TM, Hunyady, L & Gurevich, VV 2017, 'Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors', Cellular Signalling, vol. 36, pp. 98-107. https://doi.org/10.1016/j.cellsig.2017.04.021
Prokop, Susanne ; Perry, Nicole A. ; Vishnivetskiy, Sergey A. ; Toth, Andras D. ; Inoue, Asuka ; Milligan, Graeme ; Iverson, Tina M. ; Hunyady, L. ; Gurevich, Vsevolod V. / Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors. In: Cellular Signalling. 2017 ; Vol. 36. pp. 98-107.
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