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Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin a-specific role in p27KIP1 degradation

DOI: 10.1016/j.jmb.2020.166795 DOI Help

Authors: Marco Salamina (Newcastle University) , Bailey C. Montefiore (Newcastle University) , Mengxi Liu (University Grossman School of Medicine; Howard Hughes Medical Institute) , Daniel J. Wood (Newcastle University) , Richard Heath (Newcastle Universit) , James R. Ault (University of Leeds) , Lan-Zhen Wang (Newcastle University) , Svitlana Korolchuk (Newcastle University) , Arnaud Basle (Newcastle University) , Martyna Pastok (Newcastle University) , Judith Reeks (Newcastle University) , Natalie J. Tatum (Newcastle University) , Frank Sobott (University of Leeds) , Stefan T. Arold (King Abdullah University of Science and Technology (KAUST); Université de Montpellier) , Michele Pagano (University Grossman School of Medicine; Howard Hughes Medical Institute) , Martin E. M. Noble (Newcastle University) , Jane A. Endicott (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 433

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 13587 , 16970

Open Access Open Access

Abstract: The SCFSKP2 ubiquitin ligase relieves G1 checkpoint control of CDK-cyclin complexes by promoting p27KIP1 degradation. We describe reconstitution of stable complexes containing SKP1-SKP2 and CDK1-cyclin B or CDK2-cyclin A/E, mediated by the CDK regulatory subunit CKS1. We further show that a direct interaction between a SKP2 N-terminal motif and cyclin A can stabilize SKP1-SKP2-CDK2-cyclin A complexes in the absence of CKS1. We identify the SKP2 binding site on cyclin A and demonstrate the site is not present in cyclin B or cyclin E. This site is distinct from but overlapping with features that mediate binding of p27KIP1 and other G1 cyclin regulators to cyclin A. We propose that the capacity of SKP2 to engage with CDK2-cyclin A by more than one structural mechanism provides a way to fine tune the degradation of p27KIP1 and distinguishes cyclin A from other G1 cyclins to ensure orderly cell cycle progression.

Journal Keywords: cell cycle; checkpoint; protein kinase; signaling; ubiquitination

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
1-s2.0-S0022283620307208-main.pdf

Discipline Tags:

Biochemistry Chemistry Life Sciences & Biotech Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Scattering Small Angle X-ray Scattering (SAXS)