Article abstract

Nature Structural & Molecular Biology 14, 114 - 122 (2007)
Published online: 28 January 2007 | doi:10.1038/nsmb1198

Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity

Shannon M Doyle1,4, James Shorter2,4, Michal Zolkiewski3, Joel R Hoskins1, Susan Lindquist2 & Sue Wickner1

Two members of the AAA+ superfamily, ClpB and Hsp104, collaborate with Hsp70 and Hsp40 to rescue aggregated proteins. However, the mechanisms that elicit and underlie their protein-remodeling activities remain unclear. We report that for both Hsp104 and ClpB, mixtures of ATP and ATP-gammaS unexpectedly unleash activation, disaggregation and unfolding activities independent of cochaperones. Mutations reveal how remodeling activities are elicited by impaired hydrolysis at individual nucleotide-binding domains. However, for some substrates, mixtures of ATP and ATP-gammaS abolish remodeling, whereas for others, ATP binding without hydrolysis is sufficient. Remodeling of different substrates necessitates a diverse balance of polypeptide 'holding' (which requires ATP binding but not hydrolysis) and unfolding (which requires ATP hydrolysis). We suggest that this versatility in reaction mechanism enables ClpB and Hsp104 to reactivate the entire aggregated proteome after stress and enables Hsp104 to control prion inheritance.

  1. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
  2. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
  3. Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506, USA.
  4. These authors contributed equally to this work.

Correspondence to: Sue Wickner1 e-mail:

Correspondence to: Susan Lindquist2 e-mail:


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