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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Un motivo de interacción XIAP conservado en la caspasa-9 y Smac/DIABLO regula la actividad de la caspasa y la
S M Srinivasula1, R Hegde, A Saleh
1Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Nature
|March 10, 2001
Resumen
La proteína inhibidora de la apoptosis ligada al X (XIAP) se une a la caspasa-9, inhibiendo la apoptosis. La unión de la proteína Smac a XIAP interrumpe esta interacción, promoviendo la apoptosis mediante la liberación de la actividad de la caspasa-9. Esto revela un mecanismo regulador clave en la muerte celular programada.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La proteína inhibidora de la apoptosis vinculada a X (XIAP) es un regulador clave de la apoptosis, inhibiendo la actividad de la caspasa.
- Smac (DIABLO) antagoniza XIAP, promoviendo la apoptosis al aliviar la inhibición de la caspasa.
Objetivo del estudio:
- Aclarar el mecanismo molecular por el cual XIAP interactúa e inhibe la caspasa-9.
- Investigar cómo la unión de Smac a XIAP afecta la actividad de la caspasa-9 y la apoptosis.
Principales métodos:
- Mutagénesis dirigida al sitio para abrogar el procesamiento de procaspasa-9 en Asp315.5.
- Mutagénesis por deleción del péptido de enlace caspase-9.
- Análisis de la formación del complejo XIAP-caspasa-9 y ensayos de inhibición.
Principales resultados:
- XIAP se une a la terminación amino procesada del péptido de enlace caspase-9 dentro del complejo activo caspase-9-Apaf-1.
- Las mutaciones que impiden el procesamiento del enlace o la eliminación del enlace anulan la unión e inhibición de XIAP.
- El péptido de enlace Cascase-9 y la unión de Smac al dominio BIR3 de XIAP son mutuamente excluyentes, con Smac interrumpiendo la interacción entre XIAP y el enlace.
Conclusiones:
- XIAP inhibe la actividad de la caspasa-9 a través de la unión directa a su péptido vinculante procesado.
- Smac potencia la actividad de la caspasa-9 y la apoptosis mediante el desplazamiento competitivo del enlazador de la caspasa-9 del dominio BIR3 de XIAP.
- Esto identifica un mecanismo conservado que involucra interacciones de péptidos opuestos con XIAP que regulan la apoptosis.
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