Human Protein-disulfide Isomerase Is a Redox-regulated Chaperone Activated by Oxidation of Domain a*□S

Background: Human protein-disulfide isomerase (hPDI) is a key enzyme and chaperone for protein folding. Results: Oxidation of domain a releases the compact conformation of hPDI and exposes the buried substrate-binding sites facilitating its high chaperone activity. Conclusion:Oxidation of hPDI activates its chaperone activity. Significance: This study provides the first structural evidence of and mechanistic insights into the redox-regulated chaperone activity of hPDI. Protein-disulfide isomerase (PDI), with domains arranged as abbxac, is a key enzyme and chaperone localized in the endo-plasmic reticulum (ER) catalyzing oxidative folding and pre-venting misfolding/aggregation of proteins. It has been contro-versial whether the chaperone activity of PDI is redox-regulated, and themolecular basis is unclear.Here,we show that both the chaperone activity and the overall conformation of human PDI are redox-regulated. We further demonstrate that the conformational changes are triggered by the active site o