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

Tóth AD, Prokop S, Gyombolai P, Várnai P, Balla A, Gurevich VV, Hunyady L, Turu G
J Biol Chem. 2018 293 (3): 876-892

PMID: 29146594 · PMCID: PMC5777260 · DOI:10.1074/jbc.M117.813139

β-Arrestins are key regulators and signal transducers of G protein-coupled receptors (GPCRs). The interaction between receptors and β-arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether β-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 β-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, G-coupled GPCR, or epidermal growth factor receptor stimulation promotes β-arrestin2 recruitment to unliganded AT angiotensin receptor (ATR). We found that this interaction depends on the stability lock, a structure responsible for the sustained binding between GPCRs and β-arrestins, formed by phosphorylated serine-threonine clusters in the receptor's C terminus and two conserved phosphate-binding lysines in the β-arrestin2 N-domain. Using improved FlAsH-based serine-threonine clusters β-arrestin2 conformational biosensors, we also show that the stability lock not only stabilizes the receptor-β-arrestin interaction, but also governs the structural rearrangements within β-arrestins. Furthermore, we found that β-arrestin2 binds to PKC-phosphorylated ATR in a distinct active conformation, which triggers MAPK recruitment and receptor internalization. Our results provide new insights into the activation of β-arrestins and reveal their novel role in receptor cross-talk.

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

MeSH Terms (12)

Angiotensin II Animals beta-Arrestins Cercopithecus aethiops COS Cells HEK293 Cells Humans Immunoblotting Microscopy, Confocal Mitogen-Activated Protein Kinases Phosphorylation Receptors, G-Protein-Coupled

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