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Differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system
journal contribution
posted on 2023-06-09, 08:38 authored by Stephen T Hallett, Martyna W Pastok, R Marc L Morgan, Anita Wittner, Katie L I M Blundell, Ildiko Felletar, Stephen R Wedge, Chrisostomos ProdromouChrisostomos Prodromou, Martin E M Noble, Laurence PearlLaurence Pearl, Jane A EndicottSelective 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.
Funding
‘Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone system; Wellcome Trust; 095605/Z/11/Z
History
Publication status
- Published
File Version
- Published version
Journal
Cell ReportsISSN
2211-1247Publisher
ElsevierExternal DOI
Issue
5Volume
21Page range
1386-1398Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-11-06First Open Access (FOA) Date
2017-11-06First Compliant Deposit (FCD) Date
2017-11-06Usage metrics
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