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How myosin VI traps its off-state, is activated and dimerizes

Author

Listed:
  • Louise Canon

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Carlos Kikuti

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Vicente J. Planelles-Herrero

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Tianming Lin

    (University of Florida College of Medicine, PO Box 100267)

  • Franck Mayeux

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Helena Sirkia

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Young il Lee

    (University of Florida College of Medicine, PO Box 100267)

  • Leila Heidsieck

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Léonid Velikovsky

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Amandine David

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Xiaoyan Liu

    (University of Florida College of Medicine, PO Box 100267)

  • Dihia Moussaoui

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Emma Forest

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University
    École Nationale Supérieure de Chimie de Montpellier)

  • Peter Höök

    (University of Florida College of Medicine, PO Box 100267)

  • Karl J. Petersen

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Tomos E. Morgan

    (MRC Laboratory of Molecular Biology)

  • Aurélie Cicco

    (Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico-Chimie Curie)

  • Julia Sirés-Campos

    (Structure et Compartimentation Membranaire, UMR 144 CNRS/Curie Institute, PSL Research University)

  • Emmanuel Derivery

    (MRC Laboratory of Molecular Biology)

  • Daniel Lévy

    (Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico-Chimie Curie)

  • Cédric Delevoye

    (Structure et Compartimentation Membranaire, UMR 144 CNRS/Curie Institute, PSL Research University)

  • H. Lee Sweeney

    (University of Florida College of Medicine, PO Box 100267)

  • Anne Houdusse

    (Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University)

Abstract

Myosin VI (Myo6) is the only minus-end directed nanomotor on actin, allowing it to uniquely contribute to numerous cellular functions. As for other nanomotors, the proper functioning of Myo6 relies on precise spatiotemporal control of motor activity via a poorly defined off-state and interactions with partners. Our structural, functional, and cellular studies reveal key features of myosin regulation and indicate that not all partners can activate Myo6. TOM1 and Dab2 cannot bind the off-state, while GIPC1 binds Myo6, releases its auto-inhibition and triggers proximal dimerization. Myo6 partners thus differentially recruit Myo6. We solved a crystal structure of the proximal dimerization domain, and show that its disruption compromises endocytosis in HeLa cells, emphasizing the importance of Myo6 dimerization. Finally, we show that the L926Q deafness mutation disrupts Myo6 auto-inhibition and indirectly impairs proximal dimerization. Our study thus demonstrates the importance of partners in the control of Myo6 auto-inhibition, localization, and activation.

Suggested Citation

  • Louise Canon & Carlos Kikuti & Vicente J. Planelles-Herrero & Tianming Lin & Franck Mayeux & Helena Sirkia & Young il Lee & Leila Heidsieck & Léonid Velikovsky & Amandine David & Xiaoyan Liu & Dihia M, 2023. "How myosin VI traps its off-state, is activated and dimerizes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42376-2
    DOI: 10.1038/s41467-023-42376-2
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    References listed on IDEAS

    as
    1. Natalia Fili & Yukti Hari-Gupta & Ália dos Santos & Alexander Cook & Simon Poland & Simon M. Ameer-Beg & Maddy Parsons & Christopher P. Toseland, 2017. "NDP52 activates nuclear myosin VI to enhance RNA polymerase II transcription," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    2. Julien Robert-Paganin & Daniel Auguin & Anne Houdusse, 2018. "Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Rong Liu & Neil Billington & Yi Yang & Charles Bond & Amy Hong & Verl Siththanandan & Yasuharu Takagi & James R. Sellers, 2021. "A binding protein regulates myosin-7a dimerization and actin bundle assembly," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    4. Shichen Hu & Yujiao Guo & Yingli Wang & Ying Li & Tao Fu & Zixuan Zhou & Yaru Wang & Jianping Liu & Lifeng Pan, 2019. "Structure of Myosin VI/Tom1 complex reveals a cargo recognition mode of Myosin VI for tethering," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    5. Virginie Ropars & Zhaohui Yang & Tatiana Isabet & Florian Blanc & Kaifeng Zhou & Tianming Lin & Xiaoyan Liu & Pascale Hissier & Frédéric Samazan & Béatrice Amigues & Eric D. Yang & Hyokeun Park & Olen, 2016. "The myosin X motor is optimized for movement on actin bundles," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
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