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

5 years ago

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

David H Gutmann, Nicholas Rensing, Ryan L Murphy, Michael Wong, Chrisostomos Prodromou, Mehdi Mollapour, Mark R Woodford, Dimitra Bourboulia, Gennady Bratslavsky, Barry Panaretou, Adam R Blanden, Rebecca A Sager, Oleg Shapiro, Stewart N Loh, Elijah Marris, Diana M Dunn

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 essential component of the cellular homeostatic machinery in eukaryotes. 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 facilitator of Hsp90-mediated folding of kinase and non-kinase clients—including Tsc2—thereby preventing their ubiquitination and proteasomal degradation. Besides stabilizing Tsc2 and forming the mTOR-regulating TSC complex, Tsc1 plays a more general role as a co-chaperone for Hsp90 on a range of client proteins.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/embj.201796700