2. Academic Validation
  3. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients

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

  • EMBO J. 2017 Dec 15;36(24):3650-3665. doi: 10.15252/embj.201796700.
Mark R Woodford 1 2,  Rebecca A Sager 1 2 3,  Elijah Marris 1 2 3,  Diana M Dunn 1 2 3,  Adam R Blanden 2 3,  Ryan L Murphy 1 2,  Nicholas Rensing 4 5,  Oleg Shapiro 1 2,  Barry Panaretou 6,  Chrisostomos Prodromou 7,  Stewart N Loh 2 3,  David H Gutmann 4,  Dimitra Bourboulia 1 2 3,  Gennady Bratslavsky 1 2,  Michael Wong 4 5,  Mehdi Mollapour 8 2 3
Affiliations

Affiliations

  • 1 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 2 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 3 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 4 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • 5 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
  • 6 Institute of Pharmaceutical Science, King's College London, London, UK.
  • 7 Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
  • 8 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA mollapom@upstate.edu.
PMID: 29127155 DOI: 10.15252/embj.201796700
Abstract

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.

Keywords

Aha1; Tsc1; Tsc2; heat‐shock protein 90; tuberous sclerosis complex.

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