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La base molecular de CRL4DDB2/CSA ubiquitina ligasa arquitectura, la orientación y la activación de la ubiquitina

Eric S Fischer¹, Andrea Scrima, Kerstin Böhm

¹Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

|November 29, 2011

Resumen

La ligasa CRL4 ((DDB2) reconoce el ADN dañado por los rayos UV a través de DDB2, pero es inhibida por el señalosoma COP9 (CSN). La unión del ADN al DDB2 libera esta inhibición, revelando un mecanismo general para la activación de la ligasa CRL4.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología Estructural Biología estructural.
La bioquímica es la bioquímica.

Sus antecedentes:

La familia de la ubiquitina ligasa DDB1-CUL4-RBX1 (CRL4) controla las funciones celulares a través de los receptores de sustrato dedicados (DCAF).
La proteína DDB2 DCAF reconoce específicamente los dímeros de pirimidina inducidos por rayos UV, cruciales para la reparación del ADN.
Comprender la regulación del CRL4 es clave para la respuesta celular al daño del ADN.

Objetivo del estudio:

Para dilucidar el mecanismo molecular del reconocimiento mediado por DDB2 de dímeros de pirimidina de ciclobutano en la cromatina.
Determinar la base estructural para la regulación de la ligasa CRL4 (((DDB2) por el COP9 del signalosooma (CSN).
Proponer un modelo general para la activación de la ligasa CRL4.

Principales métodos:

Cristalografía de rayos X de CRL4 ((DDB2) y CRL4 ((DCAF ((WD40)) complejos.
Análisis estructural de las interacciones ligasa-inhibidor.
Análisis bioquímicos para estudiar la actividad y regulación de las enzimas.

Principales resultados:

La estructura de CRL4 (DDB2) revela un brazo de ligasa móvil, creando una zona de ubiquitinación específica alrededor del daño del ADN.
El señalosoma COP9 (CSN) inhibe no enzimáticamente el CRL4 ((DDB2) de una manera independiente del CSN5.
El daño al ADN que se une a DDB2 alivia la inhibición mediada por CSN, activando la ligasa.
CRL4 ((DCAF ((WD40)) complejos comparten características arquitectónicas conservadas.

Conclusiones:

La activación de CRL4 ((DDB2) no está mediada directamente por lesiones en el ADN, sino por el desplazamiento del CSN.
La unión del sustrato al DCAF es el desencadenante general para el desplazamiento de la CSN y la activación de la ligasa CRL4.
Este trabajo proporciona un marco para comprender la regulación de los miembros de la familia de las ligasas CRL4.

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