ScholarWorks@성균관대학교

초록

beta-arrestins (beta arrs) play a crucial role in regulating G protein-coupled receptor (GPCR) signaling and trafficking. Canonically, interactions of beta arr with the phosphorylated intracellular GPCR-tail induce a multi-step conformational transition that results in the activation of beta arr. Depending on the specific interaction pattern with the receptor, beta arrs adopt multiple conformational states, each tightly linked to a specific functional outcome of beta arr recruitment. Despite its physiological relevance, the structural determinants of beta arr activation remain poorly understood. Using a combination of molecular dynamics simulations, biochemical and cell-based experiments, we reveal how specific interactions with a chemokine receptor 7 (CXCR7) promote the unbinding of the beta arr2 C-tail-a crucial step in arrestin activation. Importantly, we observe that the expulsion of the C-tail is promoted by the displacement of a conserved arginine residue (Arg394) within the beta arr polar core, which we dub "the arginine switch." Our study uncovers a role for the arginine switch that, upon engagement, destabilizes the polar core as a crucial step in the CXCR7-induced beta arr activation.

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