@article{51a1f206a5e743949989c3286a386652,
title = "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients",
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",
author = "Woodford, {Mark R.} and Sager, {Rebecca A.} and Elijah Marris and Dunn, {Diana M.} and Blanden, {Adam R.} and Murphy, {Ryan L.} and Nicholas Rensing and Oleg Shapiro and Barry Panaretou and Chrisostomos Prodromou and Loh, {Stewart N.} and Gutmann, {David H.} and Dimitra Bourboulia and Gennady Bratslavsky and Michael Wong and Mehdi Mollapour",
note = "Funding Information: We are indebted to Dr. David J. Kwiatkowski (Brigham and Women{\textquoteright}s Hospital) and Dr Brendan D. Manning (Harvard School of Public Health) for their comments and advice on the manuscript. We are grateful to Dr. Kwiatkowski for Tsc1−/− MEF cell line, Dr. Stephen Goff (Columbia University) for c-Abl−/− MEF cell line, Dr. Brodsky (University of Pittsburgh) for CFTR plasmid, Dr. Timothy Haystead (Duke University) for SNX-2112, and Dr. Jason Gestwicki for JG-98 (University of California San Francisco). This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM124256 (M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the Wellcome Trust 095605/Z11/Z (C.P.), SUNY Upstate Medical University, Upstate Foundation, One Square Mile of Hope Foundation, Carol M. Baldwin Breast Cancer Fund (D.B., M.M.), and Urology Care Foundation-American Urological Association (M.M.). Publisher Copyright: {\textcopyright} 2017 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2017",
month = dec,
day = "15",
doi = "10.15252/embj.201796700",
language = "English",
volume = "36",
pages = "3650--3665",
journal = "EMBO Journal",
issn = "0261-4189",
number = "24",
}