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Bases estructurales de la catálisis y especificidad del sustrato del ACAT1 humano

Hongwu Qian¹, Xin Zhao², Renhong Yan^3,4

¹Department of Molecular Biology, Princeton University, Princeton, NJ, USA. hongwuq@princeton.edu.

|May 21, 2020

Resumen

Los investigadores aclararon la estructura de ACAT1 humano, una enzima involucrada en el metabolismo del colesterol y un objetivo potencial de la droga. La estructura revela túneles para la entrada de sustrato, ofreciendo información sobre su mecanismo catalítico y preferencia de sustrato.

Área de la Ciencia:

La bioquímica
Biología estructural
Enzimología

Sus antecedentes:

Las acilcoenzimas A: colesterol aciltransferasas (ACAT) son enzimas clave en la homeostasis del colesterol, pertenecientes a la familia de las O-aciltransferasas ligadas a la membrana (MBOAT).
Los ACAT catalizan la formación de ésteres de colesterol, esenciales para el almacenamiento y transporte celular del colesterol.
Los ACAT están implicados como objetivos terapéuticos para la aterosclerosis, la enfermedad de Alzheimer y el cáncer.

Objetivo del estudio:

Determinar la estructura de alta resolución del ACAT1 humano mediante el uso de microscopía criolectrónica.
Aclarar la base estructural de la actividad enzimática y la especificidad del sustrato de ACAT1.
Proporcionar información sobre el mecanismo catalítico de ACAT1 y otras enzimas de la familia MBOAT.

Principales métodos:

Microscopía criolectrónica (crio-EM) para determinar la estructura del ACAT1 humano.
Dímero de análisis de la estructura cuaternaria de los dímeros.
Análisis mutacionales guiados por la estructura para sondear las vías de entrada en el sustrato.

Principales resultados:

La estructura cryo-EM de ACAT1 humano se resolvió como un dímero de dímeros.
Cada protómero comprende nueve segmentos transmembrana, formando túneles citosólicos y transmembrana distintos.
Estos túneles convergen en el sitio activo, lo que sugiere rutas de entrada separadas para la acilcoenzima A (túnel citosólico) y el colesterol (túnel transmembrana).
Los datos bioquímicos racionalizan la preferencia de ACAT1 por las cadenas acilo insaturadas.

Conclusiones:

La estructura determinada proporciona un marco molecular para comprender la función de ACAT1.
Los túneles de entrada en el sustrato identificados ofrecen información mecanicista sobre la catálisis de ACAT1.
Este estudio avanza en nuestra comprensión del metabolismo del colesterol y proporciona una base para el diseño racional de fármacos dirigidos a ACAT1.

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