Coactivator proteins as determinants of estrogen receptor structure and function: Spectroscopic evidence for a novel coactivator-stabilized receptor conformation

Anobel Tamrazi, Kathryn E. Carlson, Alice L. Rodriguez, John A. Katzenellenbogen

Research output: Contribution to journalArticle


The direct regulation of gene transcription by nuclear receptors, such as the estrogen receptor (ER), involves not just ligand and DNA binding but the recruitment of coregulators. Typically, recruitment of p160 coactivator proteins to agonist-liganded ER is considered to be unidirectional, with ligand binding stabilizing an ER ligand binding domain (LBD) conformation that favors coactivator interaction. Using fluorophore-labeled ERα-LBDs, we present evidence for a pronounced stabilization of ER conformation that results from coactivator binding, manifest by decreased ER sensitivity to proteases and reduced conformational dynamics, as well as for the formation of a novel coactivator-stabilized (costabilized) receptor conformation, that can be conveniently monitored by the generation of an excimer emission from pyrene-labeled ERα-LBDs. This costabilized conformation may embody features required to support ER transcriptional activity. Different classes of coactivator proteins combine with estrogen agonists of different structure to elicit varying degrees of this receptor stabilization, and antagonists and coactivator binding inhibitors disfavor the costabilized conformation. Remarkably, high concentrations of coactivators engender this conformation even in apo- and antagonist-bound ERs (more so with selective ER modulators than with pure antagonists), providing an in vitro model for the development of resistance to hormone therapy in breast cancer.

Original languageEnglish (US)
Pages (from-to)1516-1528
Number of pages13
JournalMolecular Endocrinology
Issue number6
StatePublished - Jun 1 2005


ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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