Deciphering the mechanism and function of Hsp100 unfoldases from protein structure

Biochem Soc Trans. 2022 Dec 16;50(6):1725-1736. doi: 10.1042/BST20220590.


Hsp100 chaperones, also known as Clp proteins, constitute a family of ring-forming ATPases that differ in 3D structure and cellular function from other stress-inducible molecular chaperones. While the vast majority of ATP-dependent molecular chaperones promote the folding of either the nascent chain or a newly imported polypeptide to reach its native conformation, Hsp100 chaperones harness metabolic energy to perform the reverse and facilitate the unfolding of a misfolded polypeptide or protein aggregate. It is now known that inside cells and organelles, different Hsp100 members are involved in rescuing stress-damaged proteins from a previously aggregated state or in recycling polypeptides marked for degradation. Protein degradation is mediated by a barrel-shaped peptidase that physically associates with the Hsp100 hexamer to form a two-component system. Notable examples include the ClpA:ClpP (ClpAP) and ClpX:ClpP (ClpXP) proteases that resemble the ring-forming FtsH and Lon proteases, which unlike ClpAP and ClpXP, feature the ATP-binding and proteolytic domains in a single polypeptide chain. Recent advances in electron cryomicroscopy (cryoEM) together with single-molecule biophysical studies have now provided new mechanistic insight into the structure and function of this remarkable group of macromolecular machines.

Keywords: ATPase; Clp; Hsp100; chaperone; disaggregase; unfoldase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Escherichia coli Proteins* / metabolism
  • Heat-Shock Proteins / metabolism
  • Molecular Chaperones / metabolism
  • Peptides
  • Substrate Specificity


  • Escherichia coli Proteins
  • Molecular Chaperones
  • Heat-Shock Proteins
  • Peptides
  • Adenosine Triphosphate