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Bases estructurales para la activación de la señal antiviral mediada por ubiquitina mediante RIG-I
Alys Peisley1, Bin Wu1, Hui Xu2
11] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 USA [2] Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Nature
|March 5, 2014
Resumen
Las cadenas de ubiquitina se unen no covalentemente a RIG-I.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología Estructural Biología estructural.
- Inmunología Inmunología.
Sus antecedentes:
- La ubiquitina (Ub) tradicionalmente modifica las proteínas objetivo covalentemente, pero las interacciones no covalentes son cada vez más reconocidas.
- El dominio de señalización del sensor inmune innato RIG-I (2CARD) interactúa con las cadenas de ubiquitina vinculadas a K63 (K63-Ubn).
- La unión no covalente de K63-Ubn a 2CARD es crucial para su formación de tetrámeros y su señalización aguas abajo.
Objetivo del estudio:
- Para aclarar la base estructural de K63-Ubn vinculante para RIG-I 2CARD.
- Comprender el papel de las interacciones en cadena de la ubiquitina en la activación de la señalización RIG-I.
- Para investigar la interacción entre las modificaciones de la ubiquitina covalente y no covalente.
Principales métodos:
- Cristalografía de rayos X de tetramero humano RIG-I 2CARD unido a cadenas de di-ubiquitina ligadas a K63.
- Análisis estructural del complejo tetramérico.
- Ensayos funcionales para evaluar la especificidad de la unión y la activación de la señalización.
Principales resultados:
- Se determinó la estructura cristalina del tetramero RIG-I 2CARD, adoptando una conformación de "lavado de cerraduras".
- K63-Ubn se une a lo largo del borde del tetrámer, uniendo las subunidades y estabilizando la estructura.
- La avidez de unión dicta el enlace de la ubiquitina y la especificidad de la longitud de la cadena; la ubiquitinación covalente estabiliza aún más el tetramero.
Conclusiones:
- Revela un nuevo mecanismo de activación de la señal mediada por ubiquitina que involucra interacciones no covalentes.
- Destaca las funciones sinérgicas de la unión de ubiquitina covalente y no covalente en la señalización de RIG-I.
- Proporciona información estructural sobre la formación y estabilización de la plataforma de señalización RIG-I.
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