Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor

Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson, Lisa M. McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigné, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions. Arrestins are a group of proteins that regulate signaling through G protein–coupled receptors (GPCRs). They are best known as an off switch in signaling through G proteins, but they also coordinate G protein–independent signaling. Kleist et al. took advantage of an intrinsically β-arrestin–biased GPCR, atypical chemokine receptor 3 (ACKR3), to study β-arrestin recruitment. Nuclear magnetic resonance spectroscopy experiments support a role for conformational selection. The inactive state shows conformational heterogeneity at the ligand-binding pocket. Ligand binding can cause stabilization of an active state that in turn tunes the dynamics at the intracellular region to allow β-arrestin recruitment. —VV Dynamic changes to conformational ensembles at intra- and extracellular sites guide β-arrestin recruitment at a biased G protein–coupled receptor.
Original languageEnglish
Pages (from-to)222-228
Number of pages7
JournalScience
Volume377
Issue number6602
DOIs
Publication statusPublished - 8 Jul 2022

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