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
  • 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 [email protected].
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.