Protein folding drives disulfide formation

Cell. 2012 Nov 9;151(4):794-806. doi: 10.1016/j.cell.2012.09.036.


PDI catalyzes the oxidative folding of disulfide-containing proteins. However, the sequence of reactions leading to a natively folded and oxidized protein remains unknown. Here we demonstrate a technique that enables independent measurements of disulfide formation and protein folding. We find that non-native disulfides are formed early in the folding pathway and can trigger misfolding. In contrast, a PDI domain favors native disulfides by catalyzing oxidation at a late stage of folding. We propose a model for cotranslational oxidative folding wherein PDI acts as a placeholder that is relieved by the pairing of cysteines caused by substrate folding. This general mechanism can explain how PDI catalyzes oxidative folding in a variety of structurally unrelated substrates.

Publication types

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

MeSH terms

  • Disulfides
  • Microscopy, Atomic Force
  • Models, Molecular
  • Oxidation-Reduction
  • Procollagen-Proline Dioxygenase / metabolism*
  • Protein Disulfide-Isomerases / metabolism*
  • Protein Folding*
  • Proteins / chemistry
  • Proteins / metabolism


  • Disulfides
  • Proteins
  • Procollagen-Proline Dioxygenase
  • P4HB protein, human
  • Protein Disulfide-Isomerases