1. A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant A and E domains
- Author
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Alexander Stark, George Reid, Gilles Flouriot, Heike Brand, Robert B. Russell, Farzad Pakdel, Olivier Kah, Martin Kos, Frank Gannon, Dominique Manu, Michael R Hübner, Graziella Penot, Raphaël Métivier, and Stefanie Denger
- Subjects
Models, Molecular ,Transcriptional Activation ,Transcription, Genetic ,Protein Conformation ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Estrogen receptor ,Biology ,Bioinformatics ,Ligands ,Protein Structure, Secondary ,Transactivation ,Genes, Reporter ,Tumor Cells, Cultured ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Gene Silencing ,Molecular Biology ,Transrepression ,Glutathione Transferase ,Models, Genetic ,Sequence Homology, Amino Acid ,A domain ,Estrogen Receptor alpha ,Cell Biology ,beta-Galactosidase ,Precipitin Tests ,Cell biology ,Protein Structure, Tertiary ,Receptors, Estrogen ,Protein Biosynthesis ,Mutagenesis, Site-Directed ,Peptides ,Estrogen receptor alpha ,Software ,HeLa Cells ,Plasmids ,Protein Binding - Abstract
The functional interplay between different domains of estrogen receptor-alpha (ERalpha, NR3A1) is responsible for the overall properties of the full-length protein. We previously identified an interaction between the N-terminal A and C-terminal domains, which we demonstrate here to repress ligand-independent transactivation and transrepression abilities of ERalpha. Using targeted mutations based on ERalpha structural models, we determine the basis for this interaction that defines a regulatory interplay between ERalpha A domain, corepressors, and ERalpha Helix 12 for binding to the same C-terminal surface. We propose a dynamic model where binding of different ligands influences the A/D-F domain interaction and results in specific functional outcomes. This model gives insights into the dynamic properties of full-length ERalpha and into the structure of unliganded ERalpha.
- Published
- 2002