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Positively charged specificity site in cyclin B1 is essential for mitotic fidelity

Author

Listed:
  • Christian Heinzle

    (University of Konstanz
    University of Konstanz)

  • Anna Höfler

    (University of Geneva)

  • Jun Yu

    (University of Geneva)

  • Peter Heid

    (University of Konstanz
    University of Konstanz)

  • Nora Kremer

    (Faculty of Medicine, LMU)

  • Rebecca Schunk

    (University of Konstanz
    University of Konstanz)

  • Florian Stengel

    (University of Konstanz
    University of Konstanz)

  • Tanja Bange

    (Faculty of Medicine, LMU)

  • Andreas Boland

    (University of Geneva)

  • Thomas U. Mayer

    (University of Konstanz
    University of Konstanz)

Abstract

Phosphorylation of substrates by cyclin-dependent kinases (CDKs) is the driving force of cell cycle progression. Several CDK-activating cyclins are involved, yet how they contribute to substrate specificity is still poorly understood. Here, we discover that a positively charged pocket in cyclin B1, which is exclusively conserved within B-type cyclins and binds phosphorylated serine- or threonine-residues, is essential for correct execution of mitosis. HeLa cells expressing pocket mutant cyclin B1 are strongly delayed in anaphase onset due to multiple defects in mitotic spindle function and timely activation of the E3 ligase APC/C. Pocket integrity is essential for APC/C phosphorylation particularly at non-consensus CDK1 sites and full in vitro ubiquitylation activity. Our results support a model in which cyclin B1’s pocket facilitates sequential substrate phosphorylations involving initial priming events that assist subsequent pocket-dependent phosphorylations even at non-consensus CDK1 motifs.

Suggested Citation

  • Christian Heinzle & Anna Höfler & Jun Yu & Peter Heid & Nora Kremer & Rebecca Schunk & Florian Stengel & Tanja Bange & Andreas Boland & Thomas U. Mayer, 2025. "Positively charged specificity site in cyclin B1 is essential for mitotic fidelity," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55669-x
    DOI: 10.1038/s41467-024-55669-x
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    References listed on IDEAS

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    1. Suyang Zhang & Leifu Chang & Claudio Alfieri & Ziguo Zhang & Jing Yang & Sarah Maslen & Mark Skehel & David Barford, 2016. "Molecular mechanism of APC/C activation by mitotic phosphorylation," Nature, Nature, vol. 533(7602), pages 260-264, May.
    2. Jun Yu & Pierre Raia & Chloe M. Ghent & Tobias Raisch & Yashar Sadian & Simone Cavadini & Pramod M. Sabale & David Barford & Stefan Raunser & David O. Morgan & Andreas Boland, 2021. "Structural basis of human separase regulation by securin and CDK1–cyclin B1," Nature, Nature, vol. 596(7870), pages 138-142, August.
    3. Jeffrey A. Ubersax & Erika L. Woodbury & Phuong N. Quang & Maria Paraz & Justin D. Blethrow & Kavita Shah & Kevan M. Shokat & David O. Morgan, 2003. "Targets of the cyclin-dependent kinase Cdk1," Nature, Nature, vol. 425(6960), pages 859-864, October.
    4. Nadine R. Rauh & Andreas Schmidt & Jenny Bormann & Erich A. Nigg & Thomas U. Mayer, 2005. "Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation," Nature, Nature, vol. 437(7061), pages 1048-1052, October.
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