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El necrosoma RIP1/RIP3 forma un complejo de señalización amiloide funcional requerido para la necrosis programada
Jixi Li1, Thomas McQuade, Ansgar B Siemer
1Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
Cell
|July 24, 2012
Resumen
Las quinasas RIP1 y RIP3 forman fibrillas amiloides que impulsan la necrosis programada. La inhibición de estas estructuras amiloides con tintes como la tioflavina T bloquea parcialmente la necrosis, revelando un nuevo mecanismo de señalización.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología celular Biología celular.
- Biología Estructural Biología estructural.
Sus antecedentes:
- La necrosis programada inducida por el factor de necrosis tumoral (TNF, por sus siglas en inglés) involucra a las cinasas RIP1 y RIP3.
- Los mecanismos estructurales precisos que rigen la señalización de la quinasa RIP siguen siendo incompletamente entendidos.
Objetivo del estudio:
- Para investigar las bases estructurales de la formación de complejos de quinasa RIP1 y RIP3.
- Determinar el papel de los motivos de interacción homotípicos (RHIM) de RIP en el ensamblaje y la señalización de la quinasa.
- Explorar la posible participación de las estructuras amiloides en la necrosis programada.
Principales métodos:
- Técnicas biofísicas que incluyen los ensayos de unión de la tioflavina T (ThT) y el rojo del Congo (CR), el dicroísmo circular, la espectroscopia infrarroja, la difracción de rayos X y la RMN en estado sólido.
- Análisis de las mutaciones RHIM RIP1 y RIP3.
- Aislamiento y caracterización de complejos endógenos RIP1/RIP3 de células necróticas.
- Estudios in vivo de la necrosis programada.
Principales resultados:
- RIP1 y RIP3 RHIMs median la formación de las fibrillas amiloides heterodímero.
- Estas fibrillas poseen núcleos amiloides estructurados con regiones móviles flanqueantes.
- Los complejos endógenos RIP1/RIP3 exhiben características amiloides y son ultraestables.
- Los tintes amiloideos (ThT, CR, HBX) inhiben parcialmente la necrosis programada.
- Las mutaciones RHIM interrumpen la formación, la activación y la necrosis programada del complejo de la quinasa.
Conclusiones:
- Las quinasas RIP se ensamblan en estructuras amiloides que son críticas para la necrosis programada.
- La formación de amiloides es un evento estructural clave en la señalización mediada por kinasa de RIP.
- Este trabajo expande las funciones conocidas de los amiloides a los complejos de señalización celular.
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