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Conformational selection guides β-arrestin recruitment at a biased G protein-coupled receptor. Science 2022 Jul 08;377(6602):222-228

Date

07/21/2022

Pubmed ID

35857540

Pubmed Central ID

PMC9574477

DOI

10.1126/science.abj4922

Scopus ID

2-s2.0-85133822505 (requires institutional sign-in at Scopus site)   5 Citations

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.

Author List

Kleist AB, Jenjak S, Sente A, Laskowski LJ, Szpakowska M, Calkins MM, Anderson EI, McNally LM, Heukers R, Bobkov V, Peterson FC, Thomas MA, Chevigné A, Smit MJ, McCorvy JD, Babu MM, Volkman BF

Authors

John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Ligands
Magnetic Resonance Spectroscopy
Mutation
Protein Binding
Protein Conformation
Receptors, CXCR
beta-Arrestins