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Identification of Regions within the F Domain of the Human Estrogen Receptor that Are Important for Modulating Transactivation and Protein-Protein Interactions

Department of Biochemistry and Molecular Biology (A.K., M.N., S.K.), University of Chicago, Chicago, Illinois 60637; and Department of Physiology (C.Z., S.D.-C., D.F.S.), Wayne State University School of Medicine, and the Barbara Ann Karmanos Cancer Institute (J.A., D.F.S.), Detroit, Michigan 48201

Address all correspondence and requests for reprints to: Debra F. Skafar, Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, Michigan 48201. E-mail: dskafar{at}med.wayne.edu; or Shohei Koide, Department of Biochemistry and Molecular Biology, University of Chicago, 929 E. 57th, Chicago, Illinois 60637. E-mail: skoide{at}uchicago.edu.

The estrogen receptor (ER) is a biologically and clinically important ligand-modulated transcription factor. The F domain of the ER modulates its functions in a ligand-, promoter-, and cell-specific manner. To identify the region(s) responsible for these functions, we characterized the effects of serial truncations within the F domain. We found that truncating the last 16 residues of the F domain altered the activity of the human ER (hER) on an estrogen response element-driven promoter in response to estradiol or 4-hydroxytamoxifen (4-OHT), its sensitivity to overexpression of the coactivator steroid receptor coactivator-1 in mammalian cells, and its interaction with a receptor-interacting domain of the coactivator steroid receptor coactivator-1 or engineered proteins ("monobodies") that specifically bind to ER/ligand complexes in a yeast two-hybrid system. Most importantly, the ability of the ER to induce pS2 was reduced in MDA-MB-231 cells stably expressing this truncated ER vs. the wild-type ER. The region includes a distinctive segment (residues 579–584; LQKYYIT) having a high content of bulky and/or hydrophobic amino acids that was previously predicted to adopt a ß-strand-like structure. As previously reported, removal of the entire F domain was necessary to eliminate the agonist activity of 4-OHT. In addition, mutation of the vicinal glycine residues between the ligand-binding domain and F domains specifically reduced the 4-OHT-dependent interactions of the hER ligand-binding domain and F domains with monobodies. These results show that regions within the F domain of the hER selectively modulate its activity and its interactions with other proteins.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   RIP140  |  SPT6  |  p300  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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				M. T. Sonoda, L. Martinez, P. Webb, M. S. Skaf, and I. Polikarpov Ligand Dissociation from Estrogen Receptor Is Mediated by Receptor Dimerization: Evidence from Molecular Dynamics Simulations Mol. Endocrinol., July 1, 2008; 22(7): 1565 - 1578. [Abstract] [Full Text] [PDF]