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The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability

Manka, SW; Moores, CA; (2018) The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability. Nature Structural & Molecular Biology , 25 (7) pp. 607-615. 10.1038/s41594-018-0087-8. Green open access

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Abstract

Microtubules form from longitudinally and laterally assembling tubulin α–β dimers. The assembly induces strain in tubulin, resulting in cycles of microtubule catastrophe and regrowth. This ‘dynamic instability’ is governed by GTP hydrolysis that renders the microtubule lattice unstable, but it is unclear how. We used a human microtubule nucleating and stabilizing neuronal protein, doublecortin, and high-resolution cryo-EM to capture tubulin’s elusive hydrolysis intermediate GDP•Pi state, alongside the prehydrolysis analog GMPCPP state and the posthydrolysis GDP state with and without an anticancer drug, Taxol. GTP hydrolysis to GDP•Pi followed by Pi release constitutes two distinct structural transitions, causing unevenly distributed compressions of tubulin dimers, thereby tightening longitudinal and loosening lateral interdimer contacts. We conclude that microtubule catastrophe is triggered because the lateral contacts can no longer counteract the strain energy stored in the lattice, while reinforcement of the longitudinal contacts may support generation of force.

Type: Article
Title: The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41594-018-0087-8
Publisher version: https://doi.org/10.1038/s41594-018-0087-8
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, Cell Biology, ALPHA-BETA-TUBULIN, PARTICLE ELECTRON CRYOMICROSCOPY, SLOWLY HYDROLYZABLE ANALOG, GTP HYDROLYSIS, CRYOELECTRON MICROSCOPY, STABILIZING AGENTS, RESOLUTION, DOUBLECORTIN, CRYSTALLOGRAPHY, VISUALIZATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10073511
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