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Estructura y dinámica de un sistema de secreción micobacteriano de tipo VII
Catalin M Bunduc1,2,3,4, Dirk Fahrenkamp1,2,3, Jiri Wald1,2,3
1Centre for Structural Systems Biology, Hamburg, Germany.
Nature
|May 13, 2021
Resumen
Mycobacterium tuberculosis utiliza sistemas de secreción de tipo VII (T7SS) para la virulencia. Este estudio revela la estructura T7SS ESX-5, que muestra cómo la proteasa MycP5 estabiliza el complejo y sugiere un nuevo mecanismo de transporte de proteínas.
Área de la Ciencia:
- Biología estructural
- Microbiología
- Mecanismos moleculares de la enfermedad
Sus antecedentes:
- La tuberculosis por micobacterias causa millones de muertes al año.
- Los sistemas de secreción de tipo VII (T7SS) son críticos para la virulencia de M. tuberculosis y el transporte de nutrientes.
- Comprender la estructura de T7SS es clave para desarrollar nuevos medicamentos contra la tuberculosis.
Objetivo del estudio:
- Para aclarar la estructura del complejo de membrana interna T7SS intacto (ESX-5) en M. tuberculosis.
- Comprender el papel de la proteasa MycP5 en el ensamblaje y la estabilidad de T7SS.
- Proporcionar una base estructural para el desarrollo de nuevos medicamentos contra la M. tuberculosis.
Principales métodos:
- Microscopía criolectrónica (Cryo-EM) para determinar la estructura del complejo ESX-5 de 2,32-MDa.
- Ensayos de actividad de la proteasa para investigar el papel de MycP5.
- Análisis estructural comparativo de los complejos T7SS con y sin MycP5.
Principales resultados:
- El conjunto ESX-5 de 2,32-MDa está estabilizado como un trímero de dímeros por la proteasa MycP5.
- MycP5 forma un trímero que cubre una cámara periplásmica que incluye dímeros EccB5, lo que sugiere un conducto de secreción.
- Los dímeros de la ATPasa EccC5 se ensamblan debajo de la cámara, sellando el canal de secreción y exhibiendo conformaciones distintas.
Conclusiones:
- MycP5 es esencial para la integridad y estabilidad del complejo T7SS ESX-5.
- El estudio propone un nuevo mecanismo para la secreción y procesamiento de proteínas a través del T7SS.
- La estructura determinada proporciona un andamio para el diseño de terapias dirigidas contra M. tuberculosis.
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