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Myosin VI drives arrestin-independent internalization and signaling of GPCRs

Author

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  • Nishaben M. Patel

    (University of Minnesota)

  • Léa Ripoll

    (University of California, San Francisco)

  • Chloe J. Peach

    (New York University
    University of Nottingham)

  • Ning Ma

    (Beckman Research Institute of the City of Hope
    Beckman Research Institute of the City of Hope)

  • Emily E. Blythe

    (University of California, San Francisco)

  • Nagarajan Vaidehi

    (Beckman Research Institute of the City of Hope
    Beckman Research Institute of the City of Hope)

  • Nigel W. Bunnett

    (New York University)

  • Mark von Zastrow

    (University of California, San Francisco)

  • Sivaraj Sivaramakrishnan

    (University of Minnesota)

Abstract

G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs. Using the D2 dopamine receptor (D2R) as a prototype, we find that myosin VI regulates receptor endocytosis, spatiotemporal localization, and signaling. We find that access to the D2R C-tail for myosin VI-driven internalization is controlled by an interaction between the C-tail and the third intracellular loop of the receptor. Agonist efficacy, co-factors, and GIPC expression modulate this interaction to tune agonist trafficking. Myosin VI is differentially regulated by distinct GPCR C-tails, suggesting a mechanism to shape spatiotemporal signaling profiles in different ligand and physiological contexts. Our biophysical and structural insights may advance orthogonal therapeutic strategies for targeting GPCRs through cytoskeletal motor proteins.

Suggested Citation

  • Nishaben M. Patel & Léa Ripoll & Chloe J. Peach & Ning Ma & Emily E. Blythe & Nagarajan Vaidehi & Nigel W. Bunnett & Mark von Zastrow & Sivaraj Sivaramakrishnan, 2024. "Myosin VI drives arrestin-independent internalization and signaling of GPCRs," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55053-9
    DOI: 10.1038/s41467-024-55053-9
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