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

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 Moussaoui, Emma Forest, Peter Höök, Karl J. Petersen, Tomos E. Morgan, Aurélie Cicco, Julia Sirés-Campos, Emmanuel Derivery, Daniel Lévy, Cédric Delevoye, H. Lee Sweeney () and Anne Houdusse ()
Additional contact information
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42376-2

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