Catalytic activation of beta-arrestin by GPCRs
Nature. 2018-05-01; 557(7705): 381-386
DOI: 10.1038/s41586-018-0079-1
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1. Nature. 2018 May;557(7705):381-386. doi: 10.1038/s41586-018-0079-1. Epub 2018 May
2.
Catalytic activation of β-arrestin by GPCRs.
Eichel K(1)(2), Jullié D(1)(2), Barsi-Rhyne B(1)(2), Latorraca NR(3)(4)(5)(6),
Masureel M(5), Sibarita JB(7)(8), Dror RO(3)(4)(5)(6), von Zastrow M(9)(10).
Author information:
(1)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco School of Medicine, San Francisco, CA, USA.
(2)Department of Psychiatry, University of California, San Francisco School of
Medicine, San Francisco, CA, USA.
(3)Biophysics Program, Stanford University, Stanford, CA, USA.
(4)Department of Computer Science, Stanford University, Stanford, CA, USA.
(5)Department of Molecular and Cellular Physiology, Stanford University School of
Medicine, Stanford, CA, USA.
(6)Institute for Computational and Mathematical Engineering, Stanford University,
Stanford, CA, USA.
(7)Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la
Recherche Scientifique, Bordeaux, France.
(8)Interdisciplinary Institute for Neuroscience, University of Bordeaux,
Bordeaux, France.
(9)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco School of Medicine, San Francisco, CA, USA.
.
(10)Department of Psychiatry, University of California, San Francisco School of
Medicine, San Francisco, CA, USA. .
Comment in
Nature. 2018 May;557(7705):318-319.
β-arrestins are critical regulator and transducer proteins for G-protein-coupled
receptors (GPCRs). β-arrestin is widely believed to be activated by forming a
stable and stoichiometric GPCR-β-arrestin scaffold complex, which requires and is
driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and
additional mechanism of β-arrestin activation that does not require stable
GPCR-β-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 β-arrestin. This promotes capture of β-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. β-arrestin clustering in
CCSs in the absence of the upstream activating GPCR is associated with a
β-arrestin-dependent component of the cellular ERK (extracellular
signal-regulated kinase) response. These results delineate a discrete mechanism
of cellular β-arrestin function that is activated catalytically by GPCRs.
DOI: 10.1038/s41586-018-0079-1
PMCID: PMC6058965
PMID: 29720660 [Indexed for MEDLINE]