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

DOI: 10.1038/s41467-024-51135-w

Authors: Rhianna J. Rowland (Newcastle University) , Svitlana Korolchuk (Newcastle University) , Marco Salamina (Newcastle University) , Natalie J. Tatum (Newcastle University) , James R. Ault (University of Leeds) , Sam Hart (University of York) , Johan P. Turkenburg (University of York) , James N. Blaza (University of York) , Martin E. M. Noble (Newcastle University) , Jane A. Endicott (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 15

State: Published (Approved)
Published: August 2024
Diamond Proposal Number(s): 28576

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.

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 14/08/2024 14:27

Documents:
s41467-024-51135-w.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)