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

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Abstract
Hormone-activated ERs (ER and ER) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the reg- ulatory 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 recep- tor 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 ER are significantly influenced by the nature of the response element. Using a series of ER and ER 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 devel- oped to measure ER-coactivator interactions re- vealed that these different conformational states of ER and ER are functionally relevant, as they dictate receptor coactivator binding preference. Together, these results indicate that the DNA re- sponse element is a key regulator of receptor structure and biological activity and suggest the ERE sequence influences the recruitment of coac- tivators 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 recep- tors and unrelated transcription factors. (Molecular Endocrinology 16: 469-486, 2002)

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