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Base molecular de la especificidad de la lis11-poliubiquitina en la deubiquitinasa Cezanne
Tycho E T Mevissen1, Yogesh Kulathu1, Monique P C Mulder2
1Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Nature
|October 13, 2016
Resumen
La deubiquitinasa Cezanne (OTUD7B) se dirige específicamente a las cadenas de poliubiquitina vinculadas a Lys11. Esta especificidad se logra a través de cambios conformacionales asistidos por ubiquitina, revelando detalles intrincados del código de ubiquitina.
Área de la Ciencia:
- Biología molecular
- Biología celular
- La bioquímica
Sus antecedentes:
- La poliubiquitina, una modificación posterior a la traducción, regula diversos procesos celulares a través de enlaces de cadena distintos.
- El "código de ubiquitina" dicta el destino de las proteínas, con enzimas deubiquitinantes (DUB) que controlan tipos específicos de enlace.
- Los DUB del tumor ovárico (OTU) son cruciales para la señalización celular, y comprender su especificidad es clave para el sistema de ubiquitina.
Objetivo del estudio:
- Aclarar el mecanismo por el cual la deubiquitinasa Cezanne (OTUD7B) reconoce y rompe específicamente las cadenas de poliubiquitina vinculadas a Lys11.
- Obtener conocimientos fundamentales sobre el sistema de ubiquitina mediante el detalle de la especificidad de los enlaces de las OTU DUB.
Principales métodos:
- Cristalografía de rayos X de Cézanne (OTUD7B) solo y en complejo con monoubiquitin y diubiquitin ligado a Lys11.
- Espectrometría de masas de intercambio de hidrógeno y deuterio (HDX-MS) para analizar los cambios conformacionales.
- Reconstrucción detallada del ciclo enzimático.
Principales resultados:
- Cezanne (OTUD7B) muestra especificidad para las cadenas de poliubiquitina ligadas a Lys11.
- Los cambios conformacionales asistidos por ubiquitina son esenciales para la activación de la enzima.
- Si bien todos los tipos de cadenas de poliubiquitina se unen al sitio S1, solo las cadenas vinculadas a Lys11 involucran productivamente al sitio activo para el volumen de negocios catalítico.
- El estudio revela nuevos estados conformacionales tras la unión de sustratos de diubiquitina.
Conclusiones:
- Cezanne (OTUD7B) emplea un mecanismo sofisticado que implica cambios conformacionales inducidos por el sustrato para lograr la especificidad de enlace de Lys11.
- Este trabajo pone de relieve la naturaleza dinámica de los DUB y la plasticidad de sus sitios activos.
- Los hallazgos proporcionan una comprensión molecular detallada de cómo se leen y procesan códigos específicos de ubiquitina en las células.
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