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Principios estructurales de organización del eje ligando-receptor IL-17
Steven C Wilson1,2, Nathanael A Caveney1,2, Michelle Yen1,2
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|July 21, 2022
Resumen
El estudio revela la estructura de los complejos de señalización de citoquinas IL-17E, cruciales para las respuestas inmunes y las enfermedades inflamatorias. Esta estructura, que tiene un
Área de la Ciencia:
- Inmunología
- Biología estructural
- Biología molecular
Sus antecedentes:
- La familia de citoquinas y receptores de la Interleucina-17 (IL-17) es crítica en la defensa del huésped y en las condiciones inflamatorias.
- Comprender la composición y la estructura precisas de los complejos de señalización ligando-receptor IL-17 es esencial para dilucidar su función.
- La IL-17E (IL-25) es un mediador clave de la inmunidad tipo 2 y un conductor de enfermedades inflamatorias como el asma alérgica, que requiere el receptor IL-17 A (IL-17RA) e IL-17RB.
Objetivo del estudio:
- Determinar la base estructural de la señalización mediada por IL-17E.
- Investigar el ensamblaje de los complejos binarios IL-25-IL-17RB e IL-25-IL-17RB-IL-17RA.
- Comprender el papel de la IL-17RA como un componente receptor compartido en la señalización de la familia IL-17.
Principales métodos:
- Microscopía cryoelectrónica (cryo-EM) para visualizar estructuras complejas.
- Técnicas de imágenes de una sola molécula.
- Ensayos basados en células para evaluar las funcionalidades de señalización.
Principales resultados:
- El complejo ternario IL-25-IL-17RB-IL-17RA adopta una arquitectura simétrica C2.
- Una geometría de punta a punta entre IL-17RB e IL-17RA es esencial para iniciar la transducción de la señal.
- La IL-25 promueve alostéricamente la formación del complejo IL-17RB-IL-17RA a través de la interacción únicamente con IL-17RB.
- Las estructuras cryo-EM de los complejos IL-17A-IL-17RA e IL-17A-IL-17RA-IL-17RC confirman la arquitectura de punta a punta como un principio conservado en la familia de receptores IL-17.
- La IL-17RA demuestra una doble funcionalidad, actuando como un ligando directo o un co-receptor.
Conclusiones:
- La interacción de punta a punta entre IL-17RB e IL-17RA es un mecanismo fundamental para el ensamblaje de la familia de receptores IL-17 y la iniciación de la señal.
- Los conocimientos estructurales proporcionan una base para comprender la inflamación impulsada por IL-17 y desarrollar terapias dirigidas.
- La IL-17RA juega un papel versátil en diferentes vías de señalización de citoquinas IL-17.
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