Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System

T. Morán Luengo, R. Kityk, Matthias Mayer*, S.G.D. Rüdiger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Protein folding in the cell requires ATP-driven chaperone machines such as the conserved Hsp70 and Hsp90. It is enigmatic how these machines fold proteins. Here, we show that Hsp90 takes a key role in protein folding by breaking an Hsp70-inflicted folding block, empowering protein clients to fold on their own. At physiological concentrations, Hsp70 stalls productive folding by binding hydrophobic, core-forming segments. Hsp90 breaks this deadlock and restarts folding. Remarkably, neither Hsp70 nor Hsp90 alters the folding rate despite ensuring high folding yields. In fact, ATP-dependent chaperoning is restricted to the early folding phase. Thus, the Hsp70-Hsp90 cascade does not fold proteins, but instead prepares them for spontaneous, productive folding. This stop-start mechanism is conserved from bacteria to man, assigning also a general function to bacterial Hsp90, HtpG. We speculate that the decreasing hydrophobicity along the Hsp70-Hsp90 cascade may be crucial for enabling spontaneous folding.
Original languageEnglish
Pages (from-to)545-552.e9
Number of pages8
JournalMolecular Cell
Issue number3
Publication statusPublished - 3 May 2018


  • Protein Folding
  • Chaperones
  • Proteostasis
  • Hsp90
  • Hsp70
  • Luciferase
  • Folding
  • Hormone Receptor


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