Functional differences in yeast protein disulfide isomerases

PDI1 is the essential gene encoding protein disulfide isomerase in yeast. T he Saccharomyces cerevisiae genome, however, contains four other nonessenti al genes with homology to PDI1: MPD1, MPD2, EUG1, and EPS1. We have investi gated the effects of simultaneous deletions of these genes. In several case s, we found that the ability of the PDI1 homologues to restore viability to a pdi1-deleted strain when overexpressed was dependent on the presence of low endogenous levels of one or more of the other homologues, This shows th at the homologues are not functionally interchangeable. In fact, Mpd1p was the only homologue capable of carrying out all the essential functions of P di1p. Furthermore, the presence of endogenous homologues with a CXXC motif in the thioredoxin-like domain is required for suppression of a pdi1 deleti on by EUG1 (which contains two CXXS active site motifs). This underlines th e essentiality of protein disulfide isomerase-catalyzed oxidation. Most mut ant combinations show defects in carboxypeptidase Y folding as well as in g lycan modification. There are, however, no significant effects on ER-associ ated protein degradation in the various protein disulfide isomerase-deleted strains.