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

Woodford, Mark R, Sager, Rebecca A, Marris, Elijah, Dunn, Diana M, Blanden, Adam R, Murphy, Ryan L, Rensing, Nicholas, Shapiro, Oleg, Panaretou, Barry, Prodromou, Chrisostomos, Loh, Stewart N, Gutmann, David H, Bourboulia, Dimitra, Bratslavsky, Gennady, Wong, Michael and Mollapour, Mehdi (2017) Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO Journal, 36. pp. 3549-3681. ISSN 0261-4189

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QP Physiology > QP0501 Animal biochemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Chrisostomos Prodromou
Date Deposited: 13 Nov 2017 09:31
Last Modified: 02 Jul 2019 17:01
URI: http://sro.sussex.ac.uk/id/eprint/70745

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