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Cited by 457Microtubule and mitosis dynamicsCancer Treatment and PharmacologyGenetic and Kidney Cyst Diseases

Mechanistic Origin of Microtubule Dynamic Instability and Its Modulation by EB Proteins

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Zhang, Rui, Alushin, Gregory M., Brown, Alan, Nogales, Eva·2015·Cell
DOI 10.1016/j.cell.2015.07.012PMC PMC4537847
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Abstract

Microtubule (MT) dynamic instability is driven by GTP hydrolysis and regulated by microtubule-associated proteins, including the plus-end tracking end-binding protein (EB) family. We report six cryo-electron microscopy (cryo-EM) structures of MTs, at 3.5 Å or better resolution, bound to GMPCPP, GTPγS, or GDP, either decorated with kinesin motor domain after polymerization or copolymerized with EB3. Subtle changes around the E-site nucleotide during hydrolysis trigger conformational changes in α-tubulin around an "anchor point," leading to global lattice rearrangements and strain generation. Unlike the extended lattice of the GMPCPP-MT, the EB3-bound GTPγS-MT has a compacted lattice that differs in lattice twist from that of the also compacted GDP-MT. These results and the observation that EB3 promotes rapid hydrolysis of GMPCPP suggest that EB proteins modulate structural transitions at growing MT ends by recognizing and promoting an intermediate state generated during GTP hydrolysis. Our findings explain both EBs end-tracking behavior and their effect on microtubule dynamics.

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  • Measured axial spacings match the well-established expanded (83 Å) and compact (81 Å) lattice spacing described for in vitro reconstituted microtubules.

    “The measured axial spacings match the well-established expanded (83 Å) and compact (81 Å) lattice spacing described for in vitro reconstituted microtubules45–47.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [46]

    The Results section on the compacted EB3-GTPγS lattice (page unavailable) describes an extended GMPCPP-K microtubule lattice and compacted EB3-GTPγS and GDP-K lattices, supporting the distinction between expanded and compact states. The passages in our copy do not give the claimed 83 Å and 81 Å axial spacings, so those values cannot be verified from this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Measured axial repeat distances correspond closely to canonical compact and expanded lattice parameters reported in vitro and in intact cells.

    “The measured axial repeat distances correspond closely to canonical compact and expanded lattice parameters reported in vitro45–47 and in intact cells48.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [46]

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Cited by

Sorted by citations

Authors
Zhang, R., Alushin, G. M., Brown, A., & Nogales, E.
Affiliations
  • Lawrence Berkeley National Laboratory (US)
  • University of California, Berkeley (US)
  • MRC Laboratory of Molecular Biology (GB)
  • Howard Hughes Medical Institute (US)
Corresponding author
Nogales, Eva
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2015-08
Volume
162
Issue
4
Pages
849-859
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2015.07.012
PMC
PMC4537847
OpenAlex
W1785817244
Cited by
457
References
0
Citations by year
2026: 33 · 2025: 38 · 2024: 35 · 2023: 35 · 2022: 31 · 2021: 35 · 2020: 37 · 2019: 56 · 2018: 57 · 2017: 46 · 2016: 43 · 2015: 11
FWCI
25.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of General Medical Sciences (T32GM008295, P01GM051487, GM 051487)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
microtubule dynamic instability, EB3, end-binding proteins, GTP hydrolysis, microtubule lattice, nucleotide binding site, kinesin motor domain, microtubule growth, microtubule-associated proteins, cryo-EM structure
MeSH terms
Amino Acid Sequence, Animals, Microtubule-Associated Proteins, Microtubules, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Crystallography, X-Ray, Cryoelectron Microscopy, Sus scrofa

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