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Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat\u2010shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co\u2010chaperone for Hsp90 that inhibits its ATPase activity. The C\u2010terminal domain of Tsc1 (998\u20131,164\u00a0aa) 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\u2010chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1\u2010Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co\u2010chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90\u2010mediated folding of kinase and non\u2010kinase clients\u2014including Tsc2\u2014thereby preventing their ubiquitination and proteasomal degradation.<\/jats:p>","DOI":"10.15252\/embj.201796700","type":"journal-article","created":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T20:10:28Z","timestamp":1510344628000},"page":"3650-3665","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Tumor suppressor Tsc1 is a new Hsp90 co\u2010chaperone that facilitates folding of kinase and non\u2010kinase clients"],"prefix":"10.1038","volume":"36","author":[{"given":"Mark R","family":"Woodford","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A","family":"Sager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elijah","family":"Marris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R","family":"Blanden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan L","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Rensing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Panaretou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrisostomos","family":"Prodromou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart N","family":"Loh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H","family":"Gutmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Bourboulia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady","family":"Bratslavsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2144-1361","authenticated-orcid":false,"given":"Mehdi","family":"Mollapour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,10]]},"reference":[{"key":"BFEMBJ201796700_CR1","volume-title":"Methods in yeast genetics","author":"A Adams","year":"1997","unstructured":"Adams A, Gottschling DE, Kaiser CA, Stearns T (1997) Methods in yeast genetics. 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