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Cited by 2Microtubule and mitosis dynamicsHeterocyclic Compound Synthesis and BioactivityProtein Structure and Dynamics

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Structural characterization and inhibition of the interaction between ch-TOG and TACC3

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Shelford, James, Burgess, Selena G., Rostkova, Elena, Richards, Mark W., Larocque, Gabrielle, Sampson, Josephina, Tiede, Christian, Fielding, Alistair J., Daviter, Tina, Tomlinson, Darren C., Calabrese, Antonio N., Pfuhl, Mark, Bayliss, Richard, Royle, Stephen J.·2025·Journal of Cell Biology
DOI 10.1083/jcb.202407002PMC PMC11921806

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Abstract

The mitotic spindle is a bipolar array of microtubules, radiating from the poles which each contain a centrosome, embedded in pericentriolar material. Two proteins, ch-TOG and TACC3, have multiple functions at the mitotic spindle due to operating either alone, together, or in complex with other proteins. To distinguish these activities, we need new molecular tools to dissect their function. Here, we present the structure of the α-helical bundle domain of ch-TOG that mediates its interaction with TACC3 and a structural model describing the interaction, supported by biophysical and biochemical data. We have isolated Affimer tools to precisely target the ch-TOG-binding site on TACC3 in live cells, which displace ch-TOG without affecting the spindle localization of other protein complex components. Inhibition of the TACC3–ch-TOG interaction led unexpectedly to fragmentation of the pericentriolar material in metaphase cells and delayed mitotic progression, uncovering a novel role of TACC3–ch-TOG in maintaining pericentriolar material integrity during mitosis to ensure timely cell division.

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Metadata

Authors
Shelford, J., Burgess, S. G., Rostkova, E., Richards, M. W., Larocque, G., Sampson, J., Tiede, C., Fielding, A. J., Daviter, T., Tomlinson, D. C., Calabrese, A. N., Pfuhl, M., Bayliss, R., & Royle, S. J.
Affiliations
  • University of Warwick (GB)
  • University of Leeds (GB)
  • King's College London (GB)
  • Liverpool John Moores University (GB)
  • Institute of Cancer Research (GB)
Corresponding author
  • Pfuhl, Mark
  • Bayliss, Richard
  • Royle, Stephen J.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2025-03-19
Volume
224
Issue
6
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.202407002
PMC
PMC11921806
OpenAlex
W4408617308
Cited by
2
References
1
Citations by year
2026: 2
FWCI
1.00
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
Funders
  • Engineering and Physical Sciences Research Council (NS/A000055/1)
  • Cancer Research UK (C25425/A27718)
  • Biotechnology and Biological Sciences Research Council (BB/L023113/1, BB/M01116X/1, BB/M012573/1)
  • Medical Research Council (MR/X008673/1)
  • Wellcome Trust
  • Royal Society (220628/Z/20/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
TACC3, mitotic spindle, pericentriolar material, protein-protein interaction, Affimers, binding sites, protein structure, mitotic progression
MeSH terms
Binding Sites, HeLa Cells, Humans, Microtubule-Associated Proteins, Microtubules, Mitosis, Spindle Apparatus, Models, Molecular, Protein Binding, Centrosome

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