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An Electrochemiluminescence-Based Assay for MeCP2 Protein Variants
Published on: May 22, 2020
La fosforilación dependiente de la actividad de la threonina 308 de MeCP2 regula la interacción con el NCoR
Daniel H Ebert1, Harrison W Gabel, Nathaniel D Robinson
1Department of Neurobiology, Harvard Medical School, and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nature
|June 18, 2013
Resumen
El síndrome de Rett (RTT) está relacionado con las mutaciones de la proteína 2 de unión al metil-CpG (MeCP2). La fosforilación dependiente de la actividad de MeCP2 en T308 regula la expresión génica y la interacción con los co-represores, y su pérdida puede causar RTT.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Genética La genética.
- La epigenética es la epigenética.
Sus antecedentes:
- El síndrome de Rett (RTT) es un trastorno del desarrollo neurológico causado por mutaciones en el gen de la proteína 2 de unión al metil-CpG (MeCP2).
- MeCP2 es una proteína nuclear crucial para regular la transcripción génica en las neuronas y está ampliamente distribuida en todo el genoma.
Objetivo del estudio:
- Investigar el papel de la fosforilación de MeCP2 en la actividad neuronal y su posible contribución al síndrome de Rett.
- Identificar sitios específicos de fosforilación en MeCP2 y sus consecuencias funcionales.
Principales métodos:
- Se utilizó un mapeo fosfotriptico para identificar tres sitios de fosforilación dependientes de la actividad en MeCP2 (S86, S274, T308).
- Los estudios se llevaron a cabo en ratones knock-in con la mutación R306C asociada a RTT y ratones con una mutación T308A en MeCP2.
- Se analizó la interacción de MeCP2 con el complejo co-represor del receptor nuclear (NCoR) y su efecto en la transcripción génica.
Principales resultados:
- La actividad neuronal induce diferencialmente la fosforilación en S86, S274 y T308.8.
- Se encontró que la fosforilación de T308 inhibe la interacción de MeCP2 con el complejo NCoR, suprimiendo así la represión transcripcional.
- En ratones modelo RTT (mutación R306C), la fosforilación T308 no fue inducida por la actividad neuronal.
- Los ratones con una mutación T308A en MeCP2 exhibieron una reducción de la inducción de genes regulados por la actividad y síntomas similares a los de RTT.
Conclusiones:
- La fosforilación dependiente de la actividad de MeCP2 en T308 es un mecanismo clave que regula su interacción con el complejo NCoR.
- La pérdida de fosforilación de T308 puede ser un factor significativo que contribuye a la patogénesis del síndrome de Rett.
- La interrupción de esta interacción regulada por la fosforilación está implicada en la disfunción neurológica observada en RTT.
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