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Allosteric Regulation of Estrogen Receptor Structure, Function, and Coactivator Recruitment by Different Estrogen Response Elements

Receptor Biology Section (J.M.H, K.S.K), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and Department of Pharmacology and Cancer Biology Duke University Medical Center (D.P.M.), Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Dr. Kenneth Korach, Receptor Biology Section, National Institute of Environmental Health Sciences, P.O. Box 12233, MD B3-02, Research Triangle Park, North Carolina 27709. E-mail: korach{at}niehs.nih.gov.

Hormone-activated ERs (ER and ERß) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the regulatory regions of target genes. Once considered to function solely as receptor tethers, there is an increasing amount of recent evidence to suggest that the sequence of the ERE can influence receptor activity. In this study, we have performed a systematic analysis of the role of different EREs in ER pharmacology. Specifically, by measuring ER activity on the vitellogenin A2, complement 3 gene, pS2, and lactoferrin EREs, we demonstrate that the activities of E2 and xenoestrogen ligands through ER and ERß are significantly influenced by the nature of the response element. Using a series of ER and ERß interacting peptides that contain the coactivator-binding motif LXXLL, we show that the type of ERE with which the receptor associates regulates the structure of the coactivator pocket on ER. Furthermore, using a novel ELISA developed to measure ER-coactivator interactions revealed that these different conformational states of ER and ERß are functionally relevant, as they dictate receptor coactivator binding preference. Together, these results indicate that the DNA response element is a key regulator of receptor structure and biological activity and suggest the ERE sequence influences the recruitment of coactivators to the ER at target gene promoters. We propose that DNA-induced alteration of protein structure and coregulator recruitment may serve as a universal regulatory component for differential gene expression by other nuclear hormone receptors and unrelated transcription factors.

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