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

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 () and Jane A. Endicott ()
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Rhianna J. Rowland: Framlington Place
Svitlana Korolchuk: Framlington Place
Marco Salamina: Framlington Place
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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51135-w

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