Catalytic activation of beta-arrestin by GPCRs

Article

关键词: PROTEIN-COUPLED RECEPTOR;    CLATHRIN-COATED PITS;    BETA(2)-ADRENERGIC RECEPTOR;    BETA-2-ADRENERGIC RECEPTOR;    STRUCTURAL BASIS;    VISUAL ARRESTIN;    PLASMA-MEMBRANE;    AMPA RECEPTORS;    IMAGE-ANALYSIS;    ENDOCYTOSIS;   

DOI  :  10.1038/s41586-018-0079-1

来源: SCIE

【 摘 要 】

beta-arrestins are critical regulator and transducer proteins for G-protein-coupled receptors (GPCRs). beta-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-beta-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of beta-arrestin activation that does not require stable GPCR-beta-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in beta-arrestin. This promotes capture of beta-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. beta-arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a beta-arrestin-dependent component of the cellular ERK (extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular beta-arrestin function that is activated catalytically by GPCRs.

【 授权许可】

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