Plasma membrane preassociation drives β-arrestin coupling to receptors and activation

Grimes, Jak; Koszegi, Zsombor; Lanoiselée, Yann; Miljus, Tamara; O’Brien, Shannon L.; Stepniewski, Tomasz M.; Medel-Lacruz, Brian; Baidya, Mithu; Makarova, Maria; Mistry, Ravi; Goulding, Joëlle; Drube, Julia; Hoffmann, Carsten; Owen, Dylan M.; Shukla, Arun K.; Selent, Jana; Hill, Stephen J.; Calebiro, Davide

Abstract

β-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-β-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in β-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that β-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, they indicate that, following receptor interaction, the plasma membrane stabilizes β-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of β-arrestin function at the plasma membrane, revealing a critical role for β-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.

Citation

Grimes, J., Koszegi, Z., Lanoiselée, Y., Miljus, T., O’Brien, S. L., Stepniewski, T. M., …Calebiro, D. (2023). Plasma membrane preassociation drives β-arrestin coupling to receptors and activation. Cell, 186(10), 2238-2255. https://doi.org/10.1016/j.cell.2023.04.018

• Journal Article Type: Article
• Acceptance Date: Apr 12, 2023
• Online Publication Date: May 4, 2023
• Publication Date: May 11, 2023
• Deposit Date: May 5, 2023
• Publicly Available Date: May 10, 2023
• Journal: Cell
• Print ISSN: 0092-8674
• Electronic ISSN: 1097-4172
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 186
• Issue: 10
• Pages: 2238-2255
• DOI: https://doi.org/10.1016/j.cell.2023.04.018
• Keywords: G protein-coupled receptors; GPCR; arrestin; single-molecule microscopy; TIRF; protein-protein interactions; plasma membrane
• Public URL: https://nottingham-repository.worktribe.com/output/20285228
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0092867423004142