Motor domain phosphorylation increases nucleotide exchange and turns MYO6 into a faster and stronger motor

Janeska J. Jonge, Andreas Graw, Vasileios Kargas, Christopher Batters, Antonino F. Montanarella, Tom O’Loughlin, Chloe Johnson, Susan D. Arden, Alan J. Warren, Michael A. Geeves, John Kendrick-Jones, Nathan R. Zaccai, Markus Kröss, Claudia Veigel () and Folma Buss ()
Additional contact information
Janeska J. Jonge: University of Cambridge
Andreas Graw: Biomedical Centre (BMC), Ludwig-Maximilians-Universität München
Vasileios Kargas: University of Cambridge
Christopher Batters: University of Cambridge
Antonino F. Montanarella: Biomedical Centre (BMC), Ludwig-Maximilians-Universität München
Tom O’Loughlin: University of Cambridge
Chloe Johnson: University of Cambridge
Susan D. Arden: University of Cambridge
Alan J. Warren: University of Cambridge
Michael A. Geeves: University of Kent
John Kendrick-Jones: Cambridge Biomedical Campus
Nathan R. Zaccai: University of Cambridge
Markus Kröss: Biomedical Centre (BMC), Ludwig-Maximilians-Universität München
Claudia Veigel: Biomedical Centre (BMC), Ludwig-Maximilians-Universität München
Folma Buss: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Myosin motors perform many fundamental functions in eukaryotic cells by providing force generation, transport or tethering capacity. Motor activity control within the cell involves on/off switches, however, few examples are known of how myosins regulate speed or processivity and fine-tune their activity to a specific cellular task. Here, we describe a phosphorylation event for myosins of class VI (MYO6) in the motor domain, which accelerates its ATPase activity leading to a 4-fold increase in motor speed determined by actin-gliding assays, single molecule mechanics and stopped flow kinetics. We demonstrate that the serine/threonine kinase DYRK2 phosphorylates MYO6 at S267 in vitro. Single-molecule optical-tweezers studies at low load reveal that S267-phosphorylation results in faster nucleotide-exchange kinetics without change in the working stroke of the motor. The selective increase in stiffness of the acto-MYO6 complex when proceeding load-dependently into the nucleotide-free rigor state demonstrates that S267-phosphorylation turns MYO6 into a stronger motor. Finally, molecular dynamic simulations of the nucleotide-free motor reveal an alternative interaction network within insert-1 upon phosphorylation, suggesting a molecular mechanism, which regulates insert-1 positioning, turning the S267-phosphorylated MYO6 into a faster motor.

Date: 2024
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DOI: 10.1038/s41467-024-49898-3

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