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Protein Disulfide Isomerase Serves as a Molecular Chaperone to Maintain Estrogen Receptor Structure and Function

Department of Molecular and Integrative Physiology (J.R.S.-N., A.M.N.), University of Illinois, Urbana, Illinois 61801; and Department of Cell Biology (H.M. and J.R.Y.), The Scripps Institute, La Jolla, California 92037

Address all correspondence and requests for reprints to: Ann M. Nardulli, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801. E-mail: anardull{at}life.uiuc.edu.

The effects of the steroid hormone 17ß-estradiol are mediated through its interaction with the nuclear estrogen receptor (ER). Upon binding 17ß-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 ER 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 ER in MCF-7 nuclei, alters ER conformation, enhances the ER-ERE interaction in the absence and presence of an oxidizing agent, influences the ability of ER 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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