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Nat Struct Mol Biol. 2018 Jul;25(7):607-615. doi: 10.1038/s41594-018-0087-8. Epub 2018 Jul 2.

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

Author information

1
Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, London, UK. s.manka@mail.cryst.bbk.ac.uk.
2
Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, London, UK. c.moores@mail.cryst.bbk.ac.uk.

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.

PMID:
29967541
PMCID:
PMC6201834
DOI:
10.1038/s41594-018-0087-8
[Indexed for MEDLINE]
Free PMC Article

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