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. 2018 May 3;70(3):545-552.e9.
doi: 10.1016/j.molcel.2018.03.028. Epub 2018 Apr 26.

Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System


Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System

Tania Morán Luengo et al. Mol Cell. .


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.

Keywords: DnaK; Hsp70; Hsp90; HtpG; luciferase; molecular chaperones; protein folding; protein quality control; proteostasis; steroid hormone receptor.

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