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Las estructuras y el mecanismo de bloqueo del modulador de homeostasis de calcio humano 2
Wooyoung Choi1, Nicolina Clemente1, Weinan Sun2,3
1Van Andel Institute, Grand Rapids, MI, USA.
Nature
|November 29, 2019
Resumen
Los moduladores de la homeostasis de calcio (CALHM) son canales iónicos involucrados en la liberación de ATP y la función neuronal. Este estudio revela el canal CALHM2
Área de la Ciencia:
- Biología estructural
- Neurociencia molecular
- Fisiología de los canales iónicos
Sus antecedentes:
- Los moduladores de homeostasis de calcio (CALHM) son canales iónicos críticos involucrados en la liberación de ATP y la señalización neuronal.
- La disfunción CALHM está implicada en trastornos neurológicos.
- Comprender la estructura de CALHM2 es clave para dilucidar su función y disfunción.
Objetivo del estudio:
- Determinar las estructuras de alta resolución del canal humano CALHM2.
- Para aclarar el mecanismo de la inhibición del canal CALHM2 por el rojo de rutenio (RUR).
- Para revelar la arquitectura y los principios de puertas de los canales CALHM2.
Principales métodos:
- Se utilizó la crio-microscopía electrónica (cryo-EM) para obtener las estructuras de CALHM2.
- Se determinaron estructuras tanto para el estado activo libre de Ca2+ como para el estado inhibido ligado a la RUR.
- Análisis de la arquitectura del canal, simetría y cambios conformacionales en la unión de RUR.
Principales resultados:
- Se obtuvieron estructuras cryo-EM de alta resolución de CALHM2 humano en estados activos e inhibidos.
- Los canales CALHM2 forman hemicanales sin cámara y uniones de hueco.
- El enlace rojo de rutenio induce cambios conformacionales, incluido un poro contraído y una hélice S1 levantada, estabilizando un estado inhibido.
Conclusiones:
- El estudio proporciona información estructural detallada sobre la arquitectura y la simetría del canal CALHM2.
- Se propone un mecanismo de encierro de dos secciones que incluya hélices S1 y N-terminales.
- Un sitio de unión de RUR cerca de S1 explica la inhibición del canal, ofreciendo una base para comprender la función del canal CALHM2 en la salud y la enfermedad.
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