6U1N

GPCR-Beta arrestin structure in lipid bilayer

Summary for 6U1N

• Entry DOI: 10.2210/pdb6u1n/pdb
• EMDB information: 20612
• Descriptor: Muscarinic acetylcholine receptor M2, Vasopressin V2 receptor chimera, Beta-arrestin-1, Fab30 heavy chain, ... (5 entities in total)
• Functional Keywords: arrestin, gpcr, complex, signaling, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 151018.72

Authors

Staus, D.P.,Hu, H.,Robertson, M.J.,Kleinhenz, A.L.W.,Wingler, L.M.,Capel, W.D.,Latorraca, N.R.,Lefkowitz, R.J.,Skiniotis, G. (deposition date: 2019-08-16, release date: 2020-02-26, Last modification date: 2024-10-16)

Primary citation

Staus, D.P.,Hu, H.,Robertson, M.J.,Kleinhenz, A.L.W.,Wingler, L.M.,Capel, W.D.,Latorraca, N.R.,Lefkowitz, R.J.,Skiniotis, G.
Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc.
Nature, 579:297-302, 2020

PubMed Abstract: After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins. In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of β-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of β-arrestin 1 (βarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of βarr1 to phosphorylated receptor residues and insertion of the finger loop of βarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G protein complex. Moreover, the cryo-electron microscopy map reveals that the C-edge of βarr1 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, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of β-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.

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

Experimental method

ELECTRON MICROSCOPY (4 Å)