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PMID: 29720660 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Catalytic activation of β-arrestin by GPCRs.

Nature ·Vol. 557 ·No. 7705 ·2018-00-00 ·Pages 381-386

Eichel K, Jullié D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita JB, Dror RO, von Zastrow M

Abstract

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.

MeSH Terms
Animals Biocatalysis COS Cells Cell Membrane/metabolism Chlorocebus aethiops HEK293 Cells Humans Phosphatidylinositols/metabolism Protein Transport Receptors, G-Protein-Coupled/chemistry,metabolism beta-Arrestins/chemistry,metabolism
Chemicals
Phosphatidylinositols Receptors, G-Protein-Coupled beta-Arrestins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Eichel Kelsie
Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, CA, USA. | Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
Jullié Damien
Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, CA, USA. | Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
Barsi-Rhyne Benjamin
Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, CA, USA. | Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
Latorraca Naomi R
Biophysics Program, Stanford University, Stanford, CA, USA. | Department of Computer Science, Stanford University, Stanford, CA, USA. | Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. | Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
Masureel Matthieu
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Sibarita Jean-Baptiste
Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la Recherche Scientifique, Bordeaux, France. | Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, France.
Dror Ron O
Biophysics Program, Stanford University, Stanford, CA, USA. | Department of Computer Science, Stanford University, Stanford, CA, USA. | Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. | Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
von Zastrow Mark
Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, CA, USA. mark.vonzastrow@ucsf.edu. | Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, CA, USA. mark.vonzastrow@ucsf.edu.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/s41586-018-0079-1
Email
mark.vonzastrow@ucsf.edu
Published
2018-00-00
Epub
2018-00-02
Pages
381-386
Language
English
Region
England
NLM ID
0410462
PMCID
PMC6058965
Subset
IM
Grants
NIDA NIH HHS · P01 DA010154 · United States
NIDA NIH HHS · R01 DA034388 · United States
NIGMS NIH HHS · T32 GM008294 · United States
NIDA NIH HHS · R01 DA012864 · United States
NINDS NIH HHS · U01 NS103522 · United States
NIDA NIH HHS · R01 DA010711 · United States
Corrections
CommentIn
PMID: 29752449
CommentIn
PMID: 30030517
External Links
PubMed source DOI: 10.1038/s41586-018-0079-1 PMC Full Text View journal details
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