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Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90 _ Elsevi.webarchive (1.77 MB)
Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90
journal contribution
posted on 2023-06-09, 17:40 authored by Rebecca A Sager, Mark R Woodford, Sarah J Backe, Alan M Makedon, Alexander J Baker-Williams, Bryan T DiGregorio, David R Loiselle, Timothy A Haystead, Natasha E Zachara, Chrisostomos ProdromouChrisostomos Prodromou, Dimitra Bourboulia, Laura S Schmidt, W Marston Linehan, Gennady Bratslavsky, Mehdi MollapourThe molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1.
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Publication status
- Published
File Version
- Published version
Journal
Cell ReportsISSN
2211-1247Publisher
ElsevierExternal DOI
Issue
5Volume
26Page range
1344-1356.e5Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-04-29First Open Access (FOA) Date
2019-04-29First Compliant Deposit (FCD) Date
2019-04-29Usage metrics
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