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Estructura del transloco del parásito de la malaria y mecanismo de exportación del efector

Chi-Min Ho^1,2,3, Josh R Beck^4,5,6, Mason Lai²

¹The Molecular Biology Institute, University of California, Los Angeles, CA, USA.

|August 29, 2018

Resumen

Se reveló estructuralmente el mecanismo Plasmodium translocon de proteínas exportadas (PTEX), descubriendo su mecanismo para exportar proteínas efectoras de la malaria. Este descubrimiento ofrece nuevas vías para desarrollar fármacos dirigidos a este sistema de exportación de parásitos esencial.

Área de la Ciencia:

Biología estructural
Parasitología
Mecanismos moleculares

Sus antecedentes:

El complejo Plasmodium translocon de proteínas exportadas (PTEX) es vital para la exportación de proteínas efectoras del parásito de la malaria a los glóbulos rojos del huésped.
El mecanismo preciso por el cual PTEX facilita esta translocación a través de la membrana vacuolar sigue siendo en gran medida desconocido.

Objetivo del estudio:

Para aclarar la base estructural y el mecanismo del complejo de núcleo PTEX.
Comprender cómo el PTEX media el transporte de proteínas efectoras durante la infección por Plasmodium falciparum.

Principales métodos:

Para determinar las estructuras del complejo del núcleo PTEX se empleó la criomicroscopia electrónica de resolución casi atómica (criomicroscopia).
Los complejos endógenos del núcleo PTEX (EXP2, PTEX150, HSP101) fueron aislados de Plasmodium falciparum utilizando etiquetas epitópicas diseñadas por CRISPR-Cas9.
Las estructuras se capturaron tanto en los estados de "compromiso" como de "reinicio" de la translocación de la carga.

Principales resultados:

El complejo del núcleo PTEX forma un canal estático en forma de embudo a través de la membrana vacuolar, compuesto de proteínas EXP2 y PTEX150 interdigitadas.
Un hexámero AAA+ HSP101 en forma de espiral se encuentra en la parte superior del canal y sufre cambios conformacionales (compactación) para facilitar el enhebrado de proteínas.
Los bucles porosos específicos dentro de HSP101 se disocian de la carga, lo que permite el restablecimiento del translocon para los ciclos de exportación posteriores.

Conclusiones:

El estudio revela el mecanismo detallado de la exportación de proteínas efectoras de Plasmodium falciparum a través del translocon PTEX.
Los conocimientos estructurales proporcionan una base para el diseño de fármacos basados en la estructura dirigidos a este mecanismo esencial de exportación de parásitos.

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