Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in p27KIP1 Degradation. Issue 5 (5th March 2021)

• Record Type: Journal Article
• Authors: Salamina, Marco; Montefiore, Bailey C.; Liu, Mengxi; Wood, Daniel J.; Heath, Richard; Ault, James R.; Wang, Lan-Zhen; Korolchuk, Svitlana; Baslé, Arnaud; Pastok, Martyna W.; Reeks, Judith; Tatum, Natalie J.; Sobott, Frank; Arold, Stefan T.; Pagano, Michele; Noble, Martin E.M.; Endicott, Jane A.
• Is Part Of: Journal of molecular biology. Volume 433:Issue 5(2021)
• Publication Date: 2021-03-05
• Subjects: cell cycle -- checkpoint -- protein kinase -- signaling -- ubiquitination; CAIM cyclin A interacting motif -- CBF cyclin-box fold -- CDK cyclin-dependent kinase -- CKI cyclin-dependent kinase inhibitor -- CKS1 cyclin-dependent kinases regulatory subunit 1 -- DSF differential scanning fluorimetry -- GST Glutathione-S-transferase -- HDX-MS hydrogen-deuterium exchange mass spectrometry -- ITC isothermal titration calorimetry -- LRR leucine rich repeats -- RMSD root mean square deviation -- SAXS small angle X-ray scattering -- SEC size exclusion chromatography -- SKP S-phase kinase associated protein -- SPR surface plasmon resonance; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.166795
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: SKP2 engages a site on the N-terminal lobe of cyclin A. SKP2 recruits a catalytic CDK2-cyclin A to CDK2-cyclin A-CKS1-p27KIP1-SKP1-SKP2. The SKP2 and p27KIP1 binding sites on cyclin A are divergent but overlap. SKP2 engages with CDK2-cyclin A by two distinct structural mechanisms. Abstract: The SCF SKP2 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.