Scarff, CA orcid.org/0000-0001-6168-0060, Carrington, G orcid.org/0000-0003-4060-4725, Casas-Mao, D et al. (4 more authors) (2020) Structure of the shutdown state of myosin-2. Nature, 588 (1). pp. 515-520. ISSN 0028-0836
Abstract
Myosin-2 is essential for processes as diverse as cell division and muscle contraction. Dephosphorylation of its regulatory light chain promotes an inactive, ‘shutdown’ state with the filament-forming tail folded onto the two heads1, which prevents filament formation and inactivates the motors2. The mechanism by which this happens is unclear. Here we report a cryo-electron microscopy structure of shutdown smooth muscle myosin with a resolution of 6 Å in the head region. A pseudo-atomic model, obtained by flexible fitting of crystal structures into the density and molecular dynamics simulations, describes interaction interfaces at the atomic level. The N-terminal extension of one regulatory light chain interacts with the tail, and the other with the partner head, revealing how the regulatory light chains stabilize the shutdown state in different ways and how their phosphorylation would allow myosin activation. Additional interactions between the three segments of the coiled coil, the motor domains and the light chains stabilize the shutdown molecule. The structure of the lever in each head is competent to generate force upon activation. This shutdown structure is relevant to all isoforms of myosin-2 and provides a framework for understanding their disease-causing mutations.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2020, The Author(s), under exclusive licence to Springer Nature Limited. This is an author produced version of a paper published in Nature. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cell Biology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cryo EM, Image Processing (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 094231/Z/10/Z MRC (Medical Research Council) MR/R009406/1 MRC (Medical Research Council) MR/S023593/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Sep 2020 14:45 |
Last Modified: | 02 Jun 2021 00:38 |
Status: | Published |
Publisher: | Springer Nature |
Identification Number: | 10.1038/s41586-020-2990-5 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165604 |