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

Tóth, András and Prokop, Susanne and Gyombolai, Pál and Várnai, Péter and Balla, András and Hunyady, László and Turu, Gábor (2018) Heterologous phosphorylation–induced formation of a stability lock permits regulation of inactive receptors by -arrestins. JOURNAL OF BIOLOGICAL CHEMISTRY, 293 (3). pp. 876-892. ISSN 0021-9258


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-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. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Item Type: Article
Uncontrolled Keywords: PHOSPHORYLATION; Structural rearrangement; Signal transducers; Receptor activity; Phosphate binding; Phorbol myristate acetates; Inactive receptors; Epidermal growth factor receptors; COUPLED RECEPTORS; SIGNAL TRANSDUCTION; PROTEINS; Locks (fasteners); ENZYMES; Crosstalk; Chemical activation; Bins; amino acids
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
Depositing User: MTMT SWORD
Date Deposited: 16 Feb 2018 09:32
Last Modified: 16 Feb 2018 09:32

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