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Single-molecule characterization of receptor–β-arrestin interaction

December 15, 2021, 3PM

Yann LANOISELEE, University of Birmingham, Royaume-Uni

Lieu(x) :     lecture room, building 84, Ecole Polytechnique


Contact :    Antigoni Alexandrou
                    antigoni.alexandrou at

Following activation by an agonist, G protein coupled receptors (GPCRs) recruit β-arrestins, which mediate rapid signal desensitization and receptor internalization. Moreover, β-arrestins can induce non-classical signalling pathways that are distinct from those activated by G proteins. Recent structural studies have provided important atomistic details about receptor–β-arrestin interactions and β-arrestin activation. However, the mechanisms that govern receptor–β-arrestin interactions in the complexity of a living cell remain poorly understood.

Here we present a thorough dynamic characterization of receptor–β-arrestin 2 (bArr2) interactions at the plasma membrane of living cells with single-molecule detail. Using the β2-adrenergic receptor (b2ARs) as a model, we show that βArr2 mainly behaves as a membrane protein, undergoing transient interactions with β2ARs via lateral diffusion to then remain bound to the plasma membrane in an active-like conformation that allows it to reach clathrin coated pits (CCPs) without the activating receptor. Using molecular dynamics simulations and targeted mutagenesis, we identify a main lipid anchoring site in the C-edge of bArr2 and a new role of the finger loop region in mediating bArr2 catalytic activation and accumulation in CCPs. These results shed new insights into the complex sequence of events involved in β-arrestin interaction with GPCRs and activation, revealing a critical role for β-arrestin interactions with the lipid bilayer.