Protein unfolding as a switch from self-recognition to high-affinity client binding

Nat Commun. 2016 Jan 20;7:10357. doi: 10.1038/ncomms10357.


Stress-specific activation of the chaperone Hsp33 requires the unfolding of a central linker region. This activation mechanism suggests an intriguing functional relationship between the chaperone's own partial unfolding and its ability to bind other partially folded client proteins. However, identifying where Hsp33 binds its clients has remained a major gap in our understanding of Hsp33's working mechanism. By using site-specific Fluorine-19 nuclear magnetic resonance experiments guided by in vivo crosslinking studies, we now reveal that the partial unfolding of Hsp33's linker region facilitates client binding to an amphipathic docking surface on Hsp33. Furthermore, our results provide experimental evidence for the direct involvement of conditionally disordered regions in unfolded protein binding. The observed structural similarities between Hsp33's own metastable linker region and client proteins present a possible model for how Hsp33 uses protein unfolding as a switch from self-recognition to high-affinity client binding.

Publication types

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

MeSH terms

  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Fluorine-19 Magnetic Resonance Imaging / methods*
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Unfolding


  • Escherichia coli Proteins
  • HSP33 protein, E coli
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Peptides