Abstract

SummaryFollowing agonist activation, G protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G protein signaling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signaling pathways that can induce cellular responses distinct from that of G proteins2. Here we present a cryo-electron microscopy (cryoEM) structure of β-arrestin1 (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.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.