A dynamic structural model for estrogen receptor-alpha activation by ligands,emphasizing the role of interactions between distant A and E domains |
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Authors: | Métivier Raphaël Stark Alexander Flouriot Gilles Hübner Michael R Brand Heike Penot Graziella Manu Dominique Denger Stefanie Reid George Kos Martin Russell Robert B Kah Olivier Pakdel Farzad Gannon Frank |
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Institution: | EMBL, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. |
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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. |
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