Tumor suppressor Tsc1 is a new Hsp90 co‐chaperone that facilitates folding of kinase and non‐kinase clients |
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| Authors: | Elijah Marris Diana M Dunn Adam R Blanden Ryan L Murphy Nicholas Rensing Oleg Shapiro Barry Panaretou Chrisostomos Prodromou Stewart N Loh David H Gutmann Dimitra Bourboulia Gennady Bratslavsky Michael Wong Mehdi Mollapour |
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| Affiliation: | 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 |
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| 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. |
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| Keywords: | Aha1 heat‐shock protein 90 Tsc1 Tsc2 tuberous sclerosis complex |
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