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Mecanismo de activación de un complejo de canales SK-calmodulina humano elucidado por estructuras cryo-EM

Chia-Hsueh Lee¹, Roderick MacKinnon²

¹Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.

Science (New York, N.Y.)

|May 5, 2018

Resumen

Los canales de potasio activados por calcio (SK) de pequeña conductividad son cruciales para la función neuronal. Las nuevas estructuras cryo-EM revelan cómo la unión a la calmodulina abre estos canales SK esenciales.

Área de la Ciencia:

Biología molecular y celular
La neurociencia
La biofísica

Sus antecedentes:

Los canales de potasio activado por calcio (SK) de pequeña conductividad regulan la excitabilidad neuronal, la transmisión sináptica y la plasticidad.
La activación del canal SK depende de la calmodulina (CaM), pero los mecanismos precisos de unión y enlace no se comprendieron completamente.

Objetivo del estudio:

Para aclarar la base estructural de la activación del canal SK por la calmodulina.
Para determinar cómo la unión de CaM conduce a la apertura del poro del canal SK.

Principales métodos:

Se utilizó la criomicroscopia electrónica (Cryo-EM) para obtener estructuras de alta resolución.
Se determinaron las estructuras del complejo de canales SK4-CaM humano tanto en estados cerrados como activados.

Principales resultados:

Cuatro moléculas de CaM se unen a un solo tetramero de canal SK4.
El lóbulo C de CaM se une constitutivamente, mientras que el lóbulo N interactúa con el enlace S4-S5 de una manera dependiente del calcio.
Los cambios de conformación en el enlace S4-S5, impulsados por la unión de CaM, dan lugar a la apertura de los poros del canal.

Conclusiones:

El estudio revela el mecanismo de control detallado de los canales SK.
Estos conocimientos estructurales proporcionan una base para el desarrollo de la farmacología específica del canal SK.

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