ncomms12037.pdf (5.68 MB)
The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding
journal contribution
posted on 2023-06-09, 01:30 authored by Mark R Woodford, Diana M Dunn, Adam R Bladen, Dante Capriotti, David Loiselle, Chrisostomos ProdromouChrisostomos Prodromou, Barry Panaretou, Philip F Hughes, Aaron Smith, Wendi Ackerman, Timothy A Haystead, Stewart N Loh, Dimitra Bourboulia, Laura S Schmidt, W Marston Linehan, Gennady Bratslavsky, Mehdi MollapourThe ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors.
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Publication status
- Published
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- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature Publishing GroupExternal DOI
Volume
7Page range
12037Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-07-04First Open Access (FOA) Date
2016-07-04First Compliant Deposit (FCD) Date
2016-07-01Usage metrics
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