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La arquitectura del complejo MKK6-p38α define la base de la especificidad y la activación de MAPK

Pauline Juyoux¹, Ioannis Galdadas^2,3, Dorothea Gobbo^2,3

¹European Molecular Biology Laboratory (EMBL), Grenoble, France.

Science (New York, N.Y.)

|September 14, 2023

Resumen

Los investigadores modelaron la activación de p38α (proteína quinasa activada por mitógeno) por MKK6 (MAP2K). Esto revela un mecanismo dinámico de fosforilación en varios pasos crucial para la señalización inmune y el desarrollo de fármacos.

Área de la Ciencia:

Vías de señalización celular
Mecanismos moleculares de la activación de la quinasa
Interacciones proteína-proteína en la inmunidad

Sus antecedentes:

La proteína quinasa activada por mitógeno (MAPK) p38α es un regulador clave de la inflamación y las respuestas inmunes.
p38α es un objetivo farmacológico significativo, pero su mecanismo de activación por MAP2K sigue siendo poco conocido debido a la formación de complejos transitorios.

Objetivo del estudio:

Para aclarar el mecanismo molecular de la activación de p38α por su cognado MAP2K, MKK6.
Generar un modelo estructural del complejo p38α-MKK6 y comprender el proceso de fosforilación.

Principales métodos:

Microscopía crioelectrónica integrada (cryo-EM) con simulaciones de dinámica molecular (DM).
Utilizó la espectrometría de masas de intercambio de hidrógeno y deuterio (HDX-MS) y experimentos celulares.
Desarrolló un enfoque multidisciplinario para capturar complejos de quinasa transitorios.

Principales resultados:

Se demostró un mecanismo de fosforilación dinámico en varios pasos para la activación de p38α.
Se identificaron las principales interacciones catalíticamente relevantes dentro del complejo p38α-MKK6.
Se demostró que los terminales amino desordenados de MAP2K dictan la especificidad de la vía.

Conclusiones:

El estudio proporciona conocimientos estructurales y mecanicistas sin precedentes sobre un evento fundamental de fosforilación de kinasa-kinasa.
La comprensión de este mecanismo de activación puede informar el desarrollo de terapias dirigidas para enfermedades inflamatorias e inmunes.
Las regiones desordenadas MAP2K desempeñan un papel crítico en la regulación de la especificidad de la señalización.

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