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Un modelo atómico del mejorador de interferón-beta del interferosoma
Daniel Panne1, Tom Maniatis, Stephen C Harrison
1The Jack and Eileen Connors Structural Biology Laboratory, Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, 250 Longwood Avenue, Boston, MA 02115, USA.
Cell
|June 19, 2007
Resumen
El gen del interferón-beta (IFN-beta) es el
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología Estructural Biología estructural.
- Inmunología Inmunología.
Sus antecedentes:
- La activación transcripcional del gen del interferón-beta (IFN-beta) depende del ensamblaje de un complejo proteico llamado enhanceosoma.
- El enhanceosome comprende los factores de transcripción ATF-2/c-Jun, el Factor Regulador de Interferón 3 (IRF-3) / IRF-7, y el Factor Nuclear kappa - potenciador de la cadena de luz de las células B activadas (NFkappaB).
- Estos factores se unen cooperativamente al potenciador IFN-beta, reclutando coactivadores y proteínas remodeladoras de la cromatina al promotor.
Objetivo del estudio:
- Para dilucidar las bases estructurales del ensamblaje del enhanceosome y la unión del ADN.
- Comprender cómo se logra la unión cooperativa de los factores de transcripción.
- Para explicar la conservación evolutiva de la secuencia del potenciador IFN-beta.
Principales métodos:
- Se determinó la estructura cristalina de los dominios de unión al ADN de IRF-3, IRF-7 y NFkappaB unidos a la mitad del potenciador IFN-beta.
- Integró esta estructura con una estructura previamente resuelta de la otra mitad del potenciador.
- Montó un modelo completo de la arquitectura del enhanceosome en el potenciador IFN-beta.
Principales resultados:
- La asociación de ocho proteínas crea una superficie continua para la unión del elemento compuesto de ADN del potenciador IFN-beta.
- Los contactos directos proteína-proteína limitados dentro del enhanceosoma sugieren cambios en la conformación del ADN y las interacciones con los coactivadores (por ejemplo, CBP) median la unión cooperativa.
- Los extensos contactos entre el complejo proteico y casi todas las parejas de nucleótidos de ADN explican la invariancia de la secuencia del potenciador.
Conclusiones:
- El estudio proporciona un modelo estructural detallado del enhanceosoma IFN-beta.
- La unión cooperativa es facilitada por la flexión del ADN y las interacciones con los coactivadores, en lugar de las extensas interfaces proteína-proteína.
- La amplia interacción con el ADN subraya la importancia funcional y la conservación evolutiva del potenciador IFN-beta.
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