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Papers In Press, published online ahead of print December 20, 2005
Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158
Corresponding Author: weissman{at}cmp.ucsf.edu
Native disulfide bond formation in eukaryotes is dependent on protein disulfide isomerase (PDI) and its homologs, which contain varying combinations of catalytically active and inactive thioredoxin domains. However, the specific contribution of PDI to the formation of new disulfides versus reduction/rearrangement of non-native disulfides is poorly understood. We analyzed the role of individual PDI domains in disulfide bond formation in a reaction driven by their natural oxidant, Ero1p. We found that Ero1p oxidizes the isolated PDI catalytic thioredoxin domains, A and A’ at the same rate. In contrast, we found that in the context of full length PDI, there is an asymmetry in the rate of oxidation of the two active sites. This asymmetry is the result of a dual effect: an enhanced rate of oxidation of the second catalytic (A') domain and the substrate-mediated inhibition of oxidation of the first catalytic (A) domain. The specific order of thioredoxin domains in PDI is important in establishing the asymmetry in the rate of oxidation of the two active sites thus allowing A and A', two thioredoxin domains that are similar in sequence and structure, to serve opposing functional roles as a disulfide oxidase and an isomerase. These findings reveal how native disulfide folding is accomplished in the ER and provide a context for understanding the proliferation of PDI homologs with combinatorial arrangements of thioredoxin domains.
J. Biol. Chem, 10.1074/jbc.M511764200
Submitted on November 1, 2005
Revised on January 1, 1998
Accepted on November 18, 2005
Domain architecture of protein disulfide isomerase facilitates its dual role as an oxidase and an isomerase in ERO1P-mediated disulfide formation
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