Heterologous phosphorylation–induced formation of a stability lock permits regulation of inactive receptors by β-arrestins

András D. Tóth, Susanne Prokop, Pál Gyombolai, Péter Várnai, András Balla, Vsevolod V. Gurevich, X. László Hunyady, X. Gábor Turu

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18 Citations (Scopus)


-Arrestins are key regulators and signal transducers of G protein– coupled receptors (GPCRs). The interaction between receptors and -arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether -arrestins are able to bind second messenger kinase–phosphorylated, but inactive receptors as well. Because heterologous phosphorylation is a common phenomenon among GPCRs, this mode of -arrestin activation may represent a novel mechanism of signal transduction and receptor cross-talk. Here we demonstrate that activation of protein kinase C (PKC) by phorbol myristate acetate, Gq/11-coupled GPCR, or epidermal growth factor receptor stimulation promotes -arrestin2 recruitment to unliganded AT1 angiotensin receptor (AT1R). We found that this interaction depends on the stability lock, a structure responsible for the sustained binding between GPCRs and -arrestins, formed by phosphorylated serine–threonine clusters in the receptor’s C terminus and two conserved phosphate-binding lysines in the -arrestin2 N-domain. Using improved FlAsH-based serine-threonine clusters -arrestin2 conformational biosensors, we also show that the stability lock not only stabilizes the receptor–-arrestin interaction, but also governs the structural rearrangements within -arrestins. Furthermore, we found that -arrestin2 binds to PKC-phosphorylated AT1R in a distinct active conformation, which triggers MAPK recruitment and receptor internalization. Our results provide new insights into the activation of -arrestins and reveal their novel role in receptor cross-talk.

Original languageEnglish
Pages (from-to)876-892
Number of pages17
JournalJournal of Biological Chemistry
Issue number3
Publication statusPublished - Jan 19 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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