Structure of the Estrogen Receptor Dimerization Domain Bound to an Antiestrogenic Phosphotyrosyl Peptide

摘要

Estrogens are one of the major agents responsible for the development of breast cancer disease. The effects of estrogens are mediated by estrogen receptor (ER) alpha and beta. The ER interacts with specific DNA sequences (EREs) of estrogen responsive genes and modulates gene transcription. The biochemical and physiological features of the newly discovered ER beta remain largely unknown. We found that ER beta, in contrast to ER alpha, lacks the ability to induce transcriptional responses synergistically when binding to multiple copies of ERE. The events leading to ER-mediated synergistic induction of gene transcription are not well understood. We found that the N-terminal region of ER alpha, which contains transactivation function-1, is critical for the synergistic response induced by ER alpha. To understand the underlying mechanism for the low transactivity of ER beta, we examined the biochemical properties of ER. ER alpha and ER beta use the same nucleotides for DNA contacts and bind to EREs with similar affinity and preferences independent from ligands. Both receptors can interact with p160 family co-activators in a ligand-dependent manner. However, ER alpha, not ER beta, can also interact with a ligand- dependent co-factor through a distinct surface. The ability of ER alpha to differentially recruit a co-factor through distinct interacting surfaces could contribute to ER subtype-specific gene responses.