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Catalytic activation of β-arrestin by GPCRs

Author

Listed:
  • Kelsie Eichel

    (University of California, San Francisco School of Medicine
    University of California, San Francisco School of Medicine)

  • Damien Jullié

    (University of California, San Francisco School of Medicine
    University of California, San Francisco School of Medicine)

  • Benjamin Barsi-Rhyne

    (University of California, San Francisco School of Medicine
    University of California, San Francisco School of Medicine)

  • Naomi R. Latorraca

    (Stanford University
    Stanford University
    Stanford University School of Medicine
    Stanford University)

  • Matthieu Masureel

    (Stanford University School of Medicine)

  • Jean-Baptiste Sibarita

    (Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la Recherche Scientifique
    University of Bordeaux)

  • Ron O. Dror

    (Stanford University
    Stanford University
    Stanford University School of Medicine
    Stanford University)

  • Mark Zastrow

    (University of California, San Francisco School of Medicine
    University of California, San Francisco School of Medicine)

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.

Suggested Citation

  • Kelsie Eichel & Damien Jullié & Benjamin Barsi-Rhyne & Naomi R. Latorraca & Matthieu Masureel & Jean-Baptiste Sibarita & Ron O. Dror & Mark Zastrow, 2018. "Catalytic activation of β-arrestin by GPCRs," Nature, Nature, vol. 557(7705), pages 381-386, May.
    • Handle: RePEc:nat:nature:v:557:y:2018:i:7705:d:10.1038_s41586-018-0079-1
    DOI: 10.1038/s41586-018-0079-1
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    Cited by:

    1. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Ruibo Zhai & Zhuoqi Wang & Zhaofei Chai & Xiaogang Niu & Conggang Li & Changwen Jin & Yunfei Hu, 2023. "Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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