Protein disulfide isomerase serves as a molecular chaperone to maintain estrogen receptor α structure and function

The effects of the steroid hormone 17β-estradiol are mediated through its interaction with the nuclear estrogen receptor (ER). Upon binding 17β-estradiol, the ER initiates changes in gene expression through its interaction with specific DNA sequences, estrogen response elements (EREs), and recruits coregulatory proteins that influence gene expression. To better understand how estrogen-responsive genes are regulated, we have isolated and identified proteins associated with ERα when it is bound to the consensus ERE. One of these proteins, protein disulfide isomerase (PDI), has two distinct functions: acting as a molecular chaperone to maintain properly folded proteins and regulating the redox state of proteins by catalyzing the thiol-disulfide exchange reaction through two thioredoxin-like domains. Using a battery of biochemical and molecular techniques, we have demonstrated that PDI colocalizes with ERα in MCF-7 nuclei, alters ERα conformation, enhances the ERα-ERE interaction in the absence and presence of an oxidizing agent, influences the ability of ERα to mediate changes in gene expression, and associates with promoter regions of two endogenous estrogen-responsive genes. Our studies suggest that PDI plays a critical role in estrogen responsiveness by functioning as a molecular chaperone and assisting the receptor in differentially regulating target gene expression.