Protein disulfide–isomerase, a folding catalyst and a redox-regulated chaperone

• PDI is a multifunctional protein with both oxidoreductase and chaperone activities.
• PDI containing four thioredoxin-like domains shows high interdomain flexibility.
• Redox-dependent conformational changes in PDI facilitate client binding and release.
• Cooperation between PDI and its partners guarantees efficient oxidative protein folding and ER redox homeostasis.

Protein disulfide–isomerase (PDI) was the first protein-folding catalyst to be characterized, half a century ago. It plays critical roles in a variety of physiological events by displaying oxidoreductase and redox-regulated chaperone activities. This review provides a brief history of the identification of PDI as both an enzyme and a molecular chaperone and of the recent advances in studies on the structure and dynamics of PDI, the substrate binding and release, and the cooperation with its partners to catalyze oxidative protein folding and maintain ER redox homeostasis. In this review, we highlight the structural features of PDI, including the high interdomain flexibility, the multiple binding sites, the two synergic active sites, and the redox-dependent conformational changes.