Catalytic activation of [beta]-arrestin by GPCRs

[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 GPC...

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Bibliographic Details
Published in:Nature 2018, Vol.557 (7706), p.381
Main Authors: Eichel, Kelsie, Jullié, Damien, Barsi-Rhyne, Benjamin, Latorraca, Naomi R, Masureel, Matthieu, Sibarita, Jean-Baptiste, Dror, Ron O
Format: Report
Language:English
Subjects:
Arrestins
Cell membranes
Cell receptors
Clathrin
G proteins
Membrane proteins
Physiological aspects
Proteins
Online Access:Get full text
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Summary:[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.
ISSN:0028-0836
DOI:10.1038/s41586-018-0079-1