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Bases estructurales para la regulación de la actividad de las metiltransferasas de la familia MLL
Yanjing Li1,2, Jianming Han1,2, Yuebin Zhang3
1National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.
Nature
|February 18, 2016
Resumen
Los investigadores descubrieron cómo RBBP5-ASH2L activa las proteínas MLL, cruciales para la regulación genética en el desarrollo y la formación de sangre. Este hallazgo revela un mecanismo universal para la regulación de la histona metiltransferasa.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- La epigenética
Sus antecedentes:
- La familia de proteínas de la Leucemia de linaje mixto (MLL, por sus siglas en inglés) regula los genes hematopoiéticos y de desarrollo clave a través de la metilación de histonas.
- Se sabe que la actividad de la proteína MLL es estimulada por WDR5, RBBP5 y ASH2L, pero el mecanismo de regulación preciso sigue sin estar claro.
Objetivo del estudio:
- Aclarar el mecanismo molecular por el cual RBBP5 y ASH2L regulan las histonas metiltransferasas de la familia MLL.
- Comprender el tema común y la plasticidad funcional en el montaje y la regulación de la actividad de los complejos MLL.
Principales métodos:
- Análisis estructural de los heterodímeros RBBP5-ASH2L.
- Pruebas bioquímicas para determinar la activación de la proteína MLL.
- Modelado computacional para comprender el mecanismo de activación.
Principales resultados:
- Un heterodímero mínimo de RBBP5-ASH2L actúa como la unidad estructural central para la activación de la familia de proteínas MLL.
- Un mecanismo de dos pasos explica cómo se activan las proteínas MLL.
- Se identificó un mecanismo de regulación universal aplicable a la mayoría de las histonas metiltransferasas.
Conclusiones:
- El heterodímero RBBP5-ASH2L es esencial para la activación de todas las metiltransferasas de la familia MLL.
- El estudio revela un mecanismo conservado para regular la actividad de la histona metiltransferasa.
- Los hallazgos ofrecen información sobre la regulación epigenética en el desarrollo y la enfermedad.
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