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Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients

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posted on 2023-06-09, 08:29 authored by Mark R Woodford, Rebecca A Sager, Elijah Marris, Diana M Dunn, Adam R Blanden, Ryan L Murphy, Nicholas Rensing, Oleg Shapiro, Barry Panaretou, Chrisostomos ProdromouChrisostomos Prodromou, Stewart N Loh, David H Gutmann, Dimitra Bourboulia, Gennady Bratslavsky, Michael Wong, Mehdi Mollapour
The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essen- tial component of the cellular homeostatic machinery in eukary- otes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998–1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co- chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilita- tor of Hsp90-mediated folding of kinase and non-kinase clients— including Tsc2—thereby preventing their ubiquitination and proteasomal degradation.

History

Publication status

  • Published

File Version

  • Published version

Journal

EMBO Journal

ISSN

0261-4189

Publisher

Nature Publishing Group

Volume

36

Page range

3549-3681

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-11-13

First Open Access (FOA) Date

2017-11-13

First Compliant Deposit (FCD) Date

2017-11-11

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