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Cited by 159Microtubule and mitosis dynamicsCancer Treatment and PharmacologySynthesis and biological activity

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

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Manka, Szymon W., Moores, Carolyn A.·2018·Nature Structural & Molecular Biology
DOI 10.1038/s41594-018-0087-8PMC PMC6201834
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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.

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  • Such regional variation is consistent with previous studies and suggests that lattice conformation can be locally influenced by lattice-binding microtubule-associated proteins, post-translational modifications, mechanical stress, or repair processes.

    “Such regional variation is consistent with previous studies58and suggest that lattice conformation can be locally influenced by lattice-binding microtuble-associated proteins (MAPs)59–61, post-translational modifications, mechanical stress50,51, or repair processes62–66.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [50]

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  • Microtubule lattice spacing has classically been linked to nucleotide state, with expanded lattices associated with GTP-like states and compact lattices associated with GDP-tubulin.

    “Microtubule lattice spacing has classically been linked to nucleotide state, with expanded lattices associated with GTP-like states and compact lattices associated with GDP-tubulin45,50,51.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [50]

  • The classical view describes newly polymerized plus ends, where GTP-tubulin is incorporated and subsequently hydrolyzed as microtubules mature.

    “This classical view describes newly polymerized plus ends, where GTP-tubulin is incorporated and subsequently hydrolyzed as the microtubules mature45,50,51.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [50]

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Authors
Manka, S. W., & Moores, C. A.
Affiliations
University of London (GB)
Corresponding author
  • Manka, Szymon W.
  • Moores, Carolyn A.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2018-07
Volume
25
Issue
7
Pages
607-615
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-018-0087-8
PMC
PMC6201834
OpenAlex
W2809813558
Cited by
159
References
0
Citations by year
2026: 17 · 2025: 27 · 2024: 15 · 2023: 25 · 2022: 18 · 2021: 17 · 2020: 17 · 2019: 19 · 2018: 4
FWCI
7.80
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • BIROn (Birkbeck, University of London) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Medical Research Council (MR/J000973/1, MR/R000352/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
microtubule dynamic instability, GTP hydrolysis, GMPCPP, paclitaxel, doublecortin, microtubule catastrophe, microtubule nucleation, microtubule stabilization
MeSH terms
Doublecortin Domain Proteins, Guanine Nucleotides, Humans, Microtubule-Associated Proteins, Microtubules, Models, Biological, Models, Molecular, Neuropeptides, Tubulin, Cryoelectron Microscopy, GTP Phosphohydrolases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, Biophysical Phenomena

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