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Molecular interplay between HURP and Kif18A in mitotic spindle regulation
Open accessPreprint — published as 10.1038/s41467-024-53691-7
Abstract
During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imaging in vitro, we demonstrate that Kif18A motility is regulated by HURP. While sparse decoration of HURP activates the motor, higher concentrations hinder processive motility. To shed light on this behavior, we determined the binding mode of HURP to microtubules using Cryo-EM. The structure reveals that one HURP motif spans laterally across β-tubulin, while a second motif binds between adjacent protofilaments. HURP partially overlaps with the microtubule-binding site of the Kif18A motor domain, indicating that excess HURP inhibits Kif18A motility by steric exclusion. We also observed that HURP and Kif18A function together to suppress dynamics of the microtubule plus-end, providing a mechanistic basis for how they collectively serve in spindle length control.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Nogales, E., Perez-Bertoldi, J., Zhao, Y., Thawani, A., & Yildiz, A.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Berkeley (US)
- University of California Berkeley
- Corresponding author
- Nogales, Eva
- Venue
- Nature Communications
- Published
- 2024-05-29
- Volume
- 15
- Issue
- 1
- Pages
- 9687-9687
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11549086
- OpenAlex
- W4404164766
- Cited by
- 6
- References
- 1
- Citations by year
- 2026: 4 · 2025: 2
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1055017, 1617028)
- U.S. Department of Health and Human Services (R35GM136414, R35GM127018)
- University of California, San Francisco
- National Institute of General Medical Sciences (R35GM136414, R35GM127018)
- 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 › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- HURP, KIF18A, microtubule dynamics, mitosis, kinetochore microtubules, kinesin-8, microtubule stabilization, processive motility, steric exclusion, microtubule-binding site, chromosome segregation
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