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La activación mecánica abre un poro revestido de lípidos en los canales iónicos de OSCA

Yaoyao Han^1,2, Zijing Zhou^3,4, Ruitao Jin⁵

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.

|April 3, 2024

Resumen

Los canales OSCA/TMEM63 mecanosensitivos utilizan un poro proteolipídico único, con lípidos que regulan su apertura. Las estructuras revelan la apertura de subunidades independientes y un mecanismo conservado a través de los canales OSCA.

Área de la Ciencia:

La biofísica
Biología estructural
Biología molecular

Sus antecedentes:

Los canales OSCA/TMEM63 forman la familia más grande de canales iónicos mecanicamente sensibles.
Estos canales son cruciales para la mecanotransducción en plantas y mamíferos.
Comprender su mecanismo de puertas es clave para el mecanismo celular.

Objetivo del estudio:

Investigar las bases moleculares de la mecanosensibilidad del canal OSCA/TMEM63.
Determinar las estructuras de los canales OSCA/TMEM63 en diversos entornos de membrana.
Para aclarar el papel de los lípidos en el canal de entrada.

Principales métodos:

Microscopía electrónica criogénica (cryo-EM) para determinar las estructuras de 44 canales.
Reconstitución de liposomas y nanodiscos para imitar las condiciones de la membrana celular.
Ensayos funcionales y modelado computacional para apoyar los hallazgos estructurales.

Principales resultados:

Poros dilatados observados bajo tensión de membrana simulada en nanodiscos.
Estructuras de OSCA1.2 totalmente abiertas con aberturas laterales de la membrana.
Se identificó un "poro proteolipídico" donde los lípidos forman la vía de permeación iónica.
Se encontró un lípido de "enclavamiento" en OSCA3.1 que inhibe la apertura del canal.
Se ha demostrado que la mutación de los residuos de coordinación lipídica activa el OSCA3.1.

Conclusiones:

Proporcionó una visión completa del ciclo de apertura del canal OSCA.
Destacó el papel crítico de los lípidos unidos en la regulación de la función del canal.
Demostró que las subunidades individuales pueden abrirse de forma independiente, expandiendo el conocimiento de la mecanotransducción.
Ofreció conocimientos mecanicistas relevantes para las familias de proteínas TMEM16 y TMC.

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