Elucidating the mechanism of substrate recognition by the bacterial Hsp90 molecular chaperone.

Academic Article


  • Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates ("clients"). Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging. Using a partially folded protein as a model system, we find that the bacterial Hsp90 adapts its conformation to the substrate, forming a binding site that spans the middle and C-terminal domains of the chaperone. Cross-linking and NMR measurements indicate that Hsp90 binds to a large partially folded region of the substrate and significantly alters both its local and long-range structure. These findings implicate Hsp90's conformational dynamics in its ability to bind and remodel partially folded proteins. Moreover, native-state hydrogen exchange indicates that Hsp90 can also interact with partially folded states only transiently populated from within a thermodynamically stable, native-state ensemble. These results suggest a general mechanism by which Hsp90 can recognize and remodel native proteins by binding and remodeling partially folded states that are transiently sampled from within the native ensemble.
  • Authors

  • Street, Timothy O
  • Zeng, Xiaohui
  • Pellarin, Riccardo
  • Bonomi, Massimiliano
  • Sali, Andrej
  • Kelly, Mark JS
  • Chu, Feixia
  • Agard, David A
  • Status

    Publication Date

  • June 12, 2014
  • Published In


  • Bacterial Proteins
  • Binding Sites
  • HSP90 Heat-Shock Proteins
  • Hsp90
  • HtpG
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Chaperones
  • Protein Binding
  • Protein Conformation
  • chaperone
  • protein folding
  • Digital Object Identifier (doi)

    Start Page

  • 2393
  • End Page

  • 2404
  • Volume

  • 426
  • Issue

  • 12