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GPCR-Beta arrestin structure in lipid bilayer
Structural highlights
Publication Abstract from PubMedAfter activation by an agonist, G-protein-coupled receptors (GPCRs) recruit beta-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis(1). Additionally, beta-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins(2). In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of beta-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of beta-arrestin 1 (betaarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-betaarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of betaarr1 to phosphorylated receptor residues and insertion of the finger loop of betaarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein complex(3). Moreover, the cryo-electron microscopy map reveals that the C-edge of betaarr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, betaarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility. Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc.,Staus DP, Hu H, Robertson MJ, Kleinhenz ALW, Wingler LM, Capel WD, Latorraca NR, Lefkowitz RJ, Skiniotis G Nature. 2020 Jan 16. pii: 10.1038/s41586-020-1954-0. doi:, 10.1038/s41586-020-1954-0. PMID:31945772[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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