Membrane-domain compartmentalization of active GPCRs by β-arrestins through PtdIns(4,5)P₂ binding.

ABSTRACT: Upon ligand-induced activation, G-protein-coupled receptors (GPCRs) recruit β-arrestins (βarrs) to the plasma membrane, where phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) stabilizes the GPCR-βarr complex. Although PtdIns(4,5)P₂ is reported to form nanoscale clusters, the spatiotemporal dynamics of how the GPCR-βarr-PtdIns(4,5)P₂ complex assembles and organizes in living cells remain unexplored. Here we demonstrate that multiple PtdIns(4,5)P₂-binding sites on βarrs cooperatively promote GPCR-βarr assembly in membrane domains. Using molecular dynamics simulations, we identify a noncanonical (NC) PtdIns(4,5)P₂-binding site, distinct from the known canonical site. Biochemical assays confirm that both sites are essential for βarr b

SUBMITTER: Kuramoto R 

PROVIDER: S-EPMC12643926 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature