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La base estructural para la unión a la membrana y la formación de poros por el linfocito perforina
Ruby H P Law1, Natalya Lukoyanova, Ilia Voskoboinik
1Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
Nature
|November 2, 2010
Resumen
Las células asesinas naturales utilizan la perforina para matar a las células infectadas. Los investigadores determinaron la estructura cristalina de rayos X de la perforina, revelando su mecanismo de formación de poros y la inesperada orientación del dominio MACPF.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Estructural Biología estructural.
- Biología celular Biología celular.
Sus antecedentes:
- Las células asesinas naturales y los linfocitos T citotóxicos eliminan las células infectadas por virus y las células cancerosas.
- Este proceso implica la liberación de perforina y granzimas para inducir la muerte celular objetivo.
- Las mutaciones de la perforina causan linfohistiocitosis hemofagocítica familiar (tipo 2 FHL), lo que subraya su papel crítico.
Objetivo del estudio:
- Para dilucidar el mecanismo de la formación de poros de la perforina.
- Determinar la base estructural de la función de la perforina en la citotoxicidad mediada por células.
Principales métodos:
- Cristalografía de rayos X de la perforina murina monomérica.
- Reconstrucción por cryo-microscopía electrónica del poro perforado.
Principales resultados:
- La estructura cristalina de rayos X reveló la forma monomérica "en forma de llave" de la perforina con los dominios MACPF, EGF y C2.
- La microscopía criolectrónica mostró que la perforina oligomeriza para formar poros para la administración de granzima.
- Inesperadamente, el dominio MACPF en el poro está orientado de adentro hacia afuera en comparación con las proteínas CDC relacionadas.
Conclusiones:
- El estudio proporciona un mecanismo estructural detallado para la formación de poros de perforina.
- Los hallazgos revelan la flexibilidad del pliegue MACPF/CDC en la defensa inmune.
- Este trabajo ofrece nuevos conocimientos sobre el ensamblaje de las proteínas inmunes formadoras de poros como el complemento.
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