title: A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant A and E domains.
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.
authors.affiliation: EMBL, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Métivier
authors.forename: Alexander
authors.initials: A
authors.lastname: Stark
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hübner
authors.forename: Heike
authors.initials: H
authors.lastname: Brand
authors.forename: Graziella
authors.initials: G
authors.lastname: Penot
authors.forename: Dominique
authors.initials: D
authors.lastname: Manu
authors.forename: Stefanie
authors.initials: S
authors.lastname: Denger
authors.forename: George
authors.initials: G
authors.lastname: Reid
authors.forename: Martin
authors.initials: M
authors.lastname: Kos
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
authors.forename: Olivier
authors.initials: O
authors.lastname: Kah
authors.forename: Farzad
authors.initials: F
authors.lastname: Pakdel
authors.forename: Frank
authors.initials: F
authors.lastname: Gannon
mesh_terms: D000595:Amino Acid Sequence; D047628:Estrogen Receptor alpha; D020868:Gene Silencing; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D011487:Protein Conformation; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012984:Software; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D010455:Peptides; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D001616:beta-Galactosidase