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Nature. 2020 Jan 16. doi: 10.1038/s41586-020-1954-0. [Epub ahead of print]

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

Author information

1
Department of Medicine, Duke University Medical Center, Durham, North Carolina, 27710, USA.
2
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, 27710, USA.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, 94305, USA.
4
School of Life and Health Sciences, Kobilka Institute of Innovative Drug Discovery, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
5
Department of Structural Biology, Stanford University School of Medicine, Stanford, California, 94305, USA.
6
School of Medicine, University of Michigan, Ann Arbor, Michigan, 48109, USA.
7
Department of Computer Science, Stanford University, Stanford, California, 94305, USA.
8
Biophysics Program, Stanford University, Stanford, California, 94305, USA.
9
Department of Medicine, Duke University Medical Center, Durham, North Carolina, 27710, USA. lefko001@receptor-biol.duke.edu.
10
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, 27710, USA. lefko001@receptor-biol.duke.edu.
11
Department of Biochemistry, Duke University Medical Center, Durham, 27710, North Carolina, USA. lefko001@receptor-biol.duke.edu.
12
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, 94305, USA. yiorgo@stanford.edu.
13
Department of Structural Biology, Stanford University School of Medicine, Stanford, California, 94305, USA. yiorgo@stanford.edu.

Abstract

Following agonist activation, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins2. Here we present a cryo-electron microscopy (cryo-EM) structure of β-arrestin 1 (βarr1) in complex with muscarinic acetylcholine-2-receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 structure shows a multimodal network of flexible interactions, including binding of the βarr1 N domain to phosphorylated receptor residues and βarr1 finger loop insertion into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein structure3. Moreover, the cryoEM map reveals that the βarr1 C-domain edge engages the lipid bilayer. Through atomistic simulations, biophysical, biochemical, and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest the cooperative interactions of β-arrestin with both the receptor and phospholipid bilayer contribute to its functional versatility.

PMID:
31945772
DOI:
10.1038/s41586-020-1954-0

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