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

Autor: Rowland RJ; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Korolchuk S; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.; Fujifilm, Belasis Ave, Stockton-on-Tees, Billingham, TS23 1LH, UK., Salamina M; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.; Evotec (UK) Ltd., Milton, Abingdon, OX14 4RZ, UK., Tatum NJ; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Ault JR; Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK., Hart S; York Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK., Turkenburg JP; York Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK., Blaza JN; York Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK., Noble MEM; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. martin.noble@ncl.ac.uk., Endicott JA; Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. jane.endicott@ncl.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 09; Vol. 15 (1), pp. 6807. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1038/s41467-024-51135-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: