The thioredoxin superfamily in oxidative protein folding

Antioxid Redox Signal. 2014 Jul 20;21(3):457-70. doi: 10.1089/ars.2014.5849. Epub 2014 Mar 6.


Significance: The thioredoxin (Trx) superfamily proteins, including protein disulfide isomerases (PDI) and Dsb protein family, are major players in oxidative protein folding, which involves native disulfide bond formation. These proteins contain Trx folds with CXXC active sites and fulfill their physiological functions in oxidative cellular compartments such as the endoplasmic reticulum (ER) or the bacterial periplasm.

Recent advances: The structure of the Trx superfamily protein PDI has been solved by X-ray crystallography and shown to be a flexible molecule, having a horseshoe shape with a closed reduced and an open oxidized conformation, which is important for exerting its catalytic activity. Atomic force microscopy revealed that PDI works as a placeholder to prevent early non-native disulfide bond formation and further misfolding. S-nitrosylation of the active site of PDI inhibits the PDI activity and links protein misfolding to neurodegenerative diseases like Alzheimer's and Parkinson's diseases.

Critical issues: Electron transfer pathways of the oxidative protein folding show conserved Trx-like thiol-disulfide chemistry. Overall, mammalian cells have a large number of disulfide-containing proteins, the folding of which involves non-native disulfide bond isomerization. The process is sensitive to oxidative stress and ER stress.

Future directions: The correct oxidative protein folding is critical for the substrate protein stability and function, and protein misfolding is linked to, for example, neurodegenerative diseases. Further understanding on the mechanisms and specific roles of Trx superfamily proteins in oxidative protein folding may lead to drug development for the treatment of bacterial infection and various human diseases in aging and neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / metabolism
  • Aging / pathology
  • Electron Transport
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Oxidation-Reduction*
  • Protein Disulfide-Isomerases / chemistry
  • Protein Disulfide-Isomerases / metabolism
  • Protein Folding*
  • Sulfhydryl Compounds
  • Thioredoxins / chemistry
  • Thioredoxins / metabolism*


  • Sulfhydryl Compounds
  • Thioredoxins
  • Protein Disulfide-Isomerases