Richard Mandel

Plasma Membrane Protein Disulfide Isomerase: Its Role in the Translocation of Diphtheria Toxin and HIV Virus Across Endosomal and Cell Membranes

As attested by the recent publication of a monograph on protein disulfide isomerase (PDI) and related enzymes and as pointed out in its Forward by an early participant and a major contributor in this field, there has been in the last few years a spectacular expansion in work on this enzyme and in our understanding of its properties (Freedman, 1995; 1997). The first mention of a microsomal thiol-disulfide oxidoreductase, later called protein disulfide isomerase, goes back to 1963, when Anfinsen and colleagues described an enzyme capable of forming and rearranging incorrect disulfide bridges in disulfide-containing proteins, a critical step in protein synthesis (Goldberger et al., 1963). Reduced and denatured Ribonuclease A and lysozyme were the first proteins in which this function was studied and the assay based on RNase refolding became instrumental in the isolation and characterization of the enzyme. The sequence of the 57 kDa PDI published in 1985 by Edman et al. allowed to relate its oxidoreduction function to the presence of a Cys-X-X-Cys motif (-CXXC-), which had been previously characterized by Holmgren (1985) as the active site of thioredoxin (Thx). The 12 kDa Thx is known to act as hydrogen donor in the reduction of protein disulfides. The sequence homology or either side of this PDI and Thx active site motif led to the concensus that PDI had two Thx domains. About at the same time, PDI was shown to reside in the endoplasmic reticulum (ER), consistent with its involvement in the formation of correct disulfide bonds in nascent proteins.