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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Estrogen Receptor alpha
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Gene Silencing
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Genes, Reporter
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Glutathione Transferase / metabolism
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HeLa Cells
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Humans
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Ligands
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Models, Genetic
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Peptides / chemistry
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Protein Biosynthesis
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Protein Conformation
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Protein Isoforms
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptors, Estrogen / chemistry
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Receptors, Estrogen / metabolism*
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Amino Acid
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Software
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Transcription, Genetic
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Transcriptional Activation
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Tumor Cells, Cultured
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beta-Galactosidase / metabolism
Substances
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Estrogen Receptor alpha
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Ligands
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Peptides
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Protein Isoforms
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Receptors, Estrogen
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Recombinant Fusion Proteins
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Glutathione Transferase
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beta-Galactosidase