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SCF ((FBXL3) ubiquitina ligasa se dirige a los criptocromos en su bolsillo de cofactor
Weiman Xing1, Luca Busino, Thomas R Hinds
1Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Nature
|March 19, 2013
Resumen
Las estructuras del criptocromo 2 (CRY2) de los mamíferos revelan cómo FBXL3 se dirige a CRY2 para la degradación, impactando el reloj circadiano. Esta interacción, influenciada por el dinucleótido de adenina flavina (FAD) y las proteínas del período (PER), ofrece posibles objetivos farmacológicos.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Cronobiología cronobiología.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Los criptocromos (CRY) son flavoproteínas cruciales para los ritmos circadianos en los mamíferos, que regulan la transcripción génica a través de interacciones con las proteínas Period (PER).
- El complejo de ubiquitina ligasa SCF ((FBXL3) degrada las proteínas CRY, controlando el circuito de retroalimentación negativa del reloj circadiano.
- Los mecanismos precisos de las interacciones CRY-PER y el papel del dinucleótido de adenina flavina (FAD) en la función CRY siguen sin estar claros.
Objetivo del estudio:
- Para aclarar la base estructural de las interacciones de CRY2 de mamíferos con FAD y el complejo de ligasa FBXL3.
- Comprender las implicaciones funcionales de la unión de FAD y la ubiquitinación mediada por FBXL3 de CRY2.
- Identificar objetivos potenciales para la intervención farmacológica en la regulación del reloj circadiano.
Principales métodos:
- Se utilizó la cristalografía de rayos X para determinar las estructuras de CRY2 de mamíferos en estados apo, FAD y complejos FBXL3-SKP1.
- El análisis estructural se centró en la bolsa de unión de FAD y la interfaz entre las proteínas CRY2, FBXL3 y PER.
- Se implicaron ensayos bioquímicos para evaluar la interrupción de estas interacciones.
Principales resultados:
- El mamífero CRY2 exhibe la unión dinámica de FAD con un bolsillo de cofactor abierto, distinto de otros criptocromos conocidos.
- La proteína de la caja F FBXL3 se une a CRY2 a través de una interacción bipartita, ocupando el bolsillo FAD y enterrando la interfaz de unión PER.
- Esta interacción es desestabilizada tanto por FAD como por PER, lo que indica un mecanismo de regulación complejo.
Conclusiones:
- Las ideas estructurales revelan un nuevo mecanismo para la ubiquitinación y degradación de CRY2 por FBXL3.3.
- La interacción entre FAD, PERs y FBXL3 pone de relieve una regulación multifacética del reloj circadiano de los mamíferos.
- Los sitios de interacción identificados presentan objetivos potenciales para el desarrollo de fármacos para modular los ritmos circadianos.
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