Differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system

Hallett, Stephen T, Pastok, Martyna W, Morgan, R Marc L, Wittner, Anita, Blundell, Katie L I M, Felletar, Ildiko, Wedge, Stephen R, Prodromou, Chrisostomos, Noble, Martin E M, Pearl, Laurence H and Endicott, Jane A (2017) Differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system. Cell reports, 21 (5). pp. 1386-1398. ISSN 2211-1247

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (13MB)


Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Related URLs:
Depositing User: Laurence Pearl
Date Deposited: 06 Nov 2017 09:49
Last Modified: 06 Nov 2017 09:49
URI: http://srodev.sussex.ac.uk/id/eprint/70934

View download statistics for this item

📧 Request an update
Project NameSussex Project NumberFunderFunder Ref
‘Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone systemUnsetWellcome Trust095605/Z/11/Z