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To Oxidize or Isomerize, That Is the Question

Protein disulfide bond formation in vivo depends on the creation of new disulfides (oxidation) as well as the rearrangement of non-native disulfides (isomerization). Protein-disulfide isomerase plays an important role in cellular disulfide bond formation and can catalyze both oxidation and isomerization of disulfide bonds. However, the specific contribution of this enzyme to the formation of new disulfides versus the rearrangement of non-native disulfides is poorly understood.

A schematic model of oxidative protein folding in the ER.

The results presented in this Paper of the Week by Mohini S. Kulp and colleagues help to clear up some of this confusion. Protein-disulfide isomerase is composed of four thioredoxin-like domains. Domains A and A' contain active sites, whereas B and B' are catalytically inactive. Kulp et al. analyzed the role of the individual protein-disulfide isomerase domains in a reaction driven by their natural oxidant, Ero1p, a conserved protein that generates disulfides in a flavin-dependent reaction that consumes molecular oxygen. Their results strongly imply that the two functional thioredoxin domains have specific individual functions: the C-terminal A' is involved in disulfide oxidation, and the N-terminal A is involved in exchange. The authors further established that this asymmetry is not intrinsic to the individual domains but rather a function of their specific order in the full-length protein, as the individual domains show no difference in their rate of oxidation.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 876-884

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