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La estructura cristalina del complejo de activador transcripcional CLOCK:BMAL1 heterodimérico
Nian Huang1, Yogarany Chelliah, Yongli Shan
1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science (New York, N.Y.)
|June 2, 2012
Resumen
Los investigadores determinaron la estructura cristalina del complejo CLOCK:BMAL1 del ratón, revelando un heterodímero asimétrico inusual crítico para el reloj circadiano de los mamíferos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Cronobiología cronobiología.
Sus antecedentes:
- Los relojes circadianos de los mamíferos regulan ciclos fisiológicos de ~24 horas a través de bucles de retroalimentación transcripcional.
- El complejo CLOCK:BMAL1 es un activador transcripcional central en este mecanismo circadiano.
Objetivo del estudio:
- Para dilucidar la estructura a nivel atómico del complejo CLOCK:BMAL1 del ratón.
- Comprender las bases estructurales de la heterodimerización de CLOCK:BMAL1 y su papel en el ritmo circadiano.
Principales métodos:
- Se empleó cristalografía de rayos X para determinar la estructura de los dominios CLOCK:BMAL1 bHLH-PAS del ratón.
- Se realizaron estudios de mutagenesis para evaluar el impacto funcional de las interfaces de heterodimero identificadas.
Principales resultados:
- La estructura cristalina reveló un heterodímero asimétrico inusual de los dominios CLOCK:BMAL1 bHLH-PAS a una resolución de 2.3 Å.
- Se identificaron tres interfaces de proteínas distintas dentro de los dominios estrechamente entrelazados bHLH, PAS-A y PAS-B.
- Las mutaciones que interrumpieron estas interfaces alteraron la estabilidad, actividad y periodicidad del oscilador circadiano del complejo CLOCK:BMAL1.
Conclusiones:
- La estructura determinada proporciona información a nivel atómico sobre el complejo CLOCK:BMAL1.
- Los hallazgos estructurales destacan la importancia de las interfaces específicas de heterodimero para la función del reloj circadiano.
- Este trabajo sirve como base para futuros estudios mecanicistas del reloj circadiano de los mamíferos.
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