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Cryo-EM structure of the CDK2-cyclin A-CDC25A complex

Author

Listed:
  • Rhianna J. Rowland

    (Framlington Place)

  • Svitlana Korolchuk

    (Framlington Place
    Stockton-on-Tees)

  • Marco Salamina

    (Framlington Place
    Milton)

  • Natalie J. Tatum

    (Framlington Place)

  • James R. Ault

    (University of Leeds)

  • Sam Hart

    (Heslington)

  • Johan P. Turkenburg

    (Heslington)

  • James N. Blaza

    (Heslington)

  • Martin E. M. Noble

    (Framlington Place)

  • Jane A. Endicott

    (Framlington Place)

Abstract

The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.

Suggested Citation

  • Rhianna J. Rowland & Svitlana Korolchuk & Marco Salamina & Natalie J. Tatum & James R. Ault & Sam Hart & Johan P. Turkenburg & James N. Blaza & Martin E. M. Noble & Jane A. Endicott, 2024. "Cryo-EM structure of the CDK2-cyclin A-CDC25A complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51135-w
    DOI: 10.1038/s41467-024-51135-w
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    References listed on IDEAS

    as
    1. Katerina Naydenova & Christopher J. Russo, 2017. "Measuring the effects of particle orientation to improve the efficiency of electron cryomicroscopy," Nature Communications, Nature, vol. 8(1), pages 1-5, December.
    2. Nicholas R. Brown & Svitlana Korolchuk & Mathew P. Martin & Will A. Stanley & Rouslan Moukhametzianov & Martin E. M. Noble & Jane A. Endicott, 2015. "CDK1 structures reveal conserved and unique features of the essential cell cycle CDK," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    3. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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