Pallav Kosuri, Jorge Alegre-Cebollada, Jason Feng, Anna Kaplan, Alvaro Inglés-Prieto, Carmen L. Badilla, Brent R. Stockwell, Jose M. Sanchez-Ruiz, Arne Holmgren, Julio M. Fernández
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.
DOI
Journal: Cell
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