The Principal Investigators (PIs) propose to study the role of protein folding chaperones in the secretion of foreign proteins from yeast. There is evidence in the literature that protein folding in the lumen of the endoplasmic reticulum may be the rate-limiting step in the overall process of secretion, and that chaperones such as protein disulfide isomerase (PDI) and KAR2 (the yeast homolog of mammalian heavy chain binding protein) play a key role in intracellular protein folding. The PIs plan to vary intracellular levels of PDI and KAR2 by use of regulated promoters, and to determine the resulting effects on foreign protein secretion. The PIs also plan to isolate novel chaperones by screening recombinant DNA libraries for genes whose overexpression enhances foreign protein secretion or complements a genetically induced defect in protein translocation into the secretory pathway.