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

Rowland, R. J.; Korolchuk, S.; Salamina, M.; Ault, J. R.; Hart, S.; Turkenberg, J. P.; Blaza, J. N.; Noble, M. E.; Endicott, J. A.

doi:10.1101/2023.10.17.562665

bioRxiv · 10.1101/2023.10.17.562665

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

Rowland, R. J.·Korolchuk, S.·Salamina, M.·Ault, J. R.·Hart, S.·Turkenberg, J. P.·Blaza, J. N.·Noble, M. E.·Endicott, J. A.

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Abstract

The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich motif of cyclin-dependent protein kinases (CDKs) to activate CDK activity. Here, we present the cryogenic-electron microscopy (cryo-EM) structure of CDK2-cyclin A in complex with CDC25A at 2.91 [A] resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further reveal an unanticipated 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.

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Rowland, R. J., Korolchuk, S., Salamina, M., Ault, J. R., Hart, S., Turkenberg, J. P., Blaza, J. N., Noble, M. E., Endicott, J. A.. 2023-10-17. Cryo-EM structure of the CDK2-cyclin A-CDC25A complex. https://doi.org/10.1101/2023.10.17.562665

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