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Bases estructurales para la inhibición de la actividad de la tirosina quinasa de ZAP-70
Sebastian Deindl1, Theresa A Kadlecek, Tomas Brdicka
1Department of Molecular and Cell Biology, Department of Chemistry, and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.
Cell
|May 22, 2007
Resumen
La activación de la quinasa ZAP-70 incluye distintos mecanismos autoinhibidores. La desestabilización de las interacciones entre su segmento regulador y el dominio de la quinasa es clave para iniciar la señalización del receptor de células T.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Inmunología Inmunología.
- Biología Estructural Biología estructural.
Sus antecedentes:
- ZAP-70 (proteína quinasa asociada a la cadena zeta 70) es una quinasa tirosina citoplasmática crucial en la señalización del receptor de antígeno de células T (TCR).
- Su actividad está regulada por un segmento que contiene dominios en tándem SH2 que se unen a los motivos de activación basados en tirosina de los inmunorreceptores (ITAM).
Objetivo del estudio:
- Para aclarar las bases estructurales de la autoinhibición ZAP-70.
- Comprender el mecanismo de activación de ZAP-70 en la señalización de las células T.
Principales métodos:
- Determinación de la estructura cristalina del ZAP-70 autoinhibido.
- Se analizaron las interacciones dentro del segmento regulador y el dominio de la quinasa.
Principales resultados:
- El dominio inactivo de la cinasa ZAP-70 adopta una conformación similar a las CDK y Src.
- La autoinhibición implica interacciones únicas entre el segmento regulador y la región de la bisagra, reduciendo la flexibilidad de la quinasa.
- Los residuos de tirosina fosforilables en el enlazador de la SH2-cinasa participan en interacciones aromáticas-aromáticas, lo que dificulta la unión de ITAM.
Conclusiones:
- El mecanismo autoinhibidor de ZAP-70 es distinto de otras quinasas.
- La desestabilización de la conformación autoinhibida a través de la interrupción de estas interacciones aromáticas es probablemente el paso inicial en la activación de ZAP-70.
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