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La base estructural y las reglas de secuencia para el reconocimiento de sustratos por Tankyrase explican la base de
Sebastian Guettler1, Jose LaRose, Evangelia Petsalaki
1Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Cell
|December 14, 2011
Resumen
Los investigadores descubrieron las reglas vinculantes para las enzimas Tankyrase (TNKS / TNKS2), cruciales para la regulación de las proteínas y vinculadas al querubinismo. Este descubrimiento aclara cómo las Tankirasas reconocen sustratos y explica las mutaciones de enfermedades.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Biología Estructural Biología estructural.
Sus antecedentes:
- La tanquirasas 1/2 (TNKS/TNKS2) son enzimas que catalizan la ADP-ribosilación, afectando la ubicuidad, la estabilidad y la función de las proteínas.
- La desregulación del reconocimiento del sustrato del TNKS está implicada en la enfermedad humana del querubinismo.
- Las enzimas TNKS utilizan grupos de repetición de ankyrin (ARC) para unirse a motivos de sustrato específicos (hexapéptidos RxxPDG).
Objetivo del estudio:
- Para determinar la base estructural del reconocimiento del sustrato de Tankyrase.
- Para derivar una secuencia de consenso para la unión de sustrato TNKS a través de ARCs conservados.
- Racionalizar los sustratos conocidos de TNKS y explicar las mutaciones relacionadas con el querubinismo.
Principales métodos:
- Las estructuras cristalinas de un grupo de repetición de ankyrin TNKS2 (ARC) unido a seis péptidos de sustrato.
- Selección de bibliotecas de péptidos basadas en soluciones para identificar secuencias de consenso de sustrato.
- Análisis bioinformático y validación experimental de los objetivos predichos de TNKS.
Principales resultados:
- Las estructuras cristalinas reportadas de un ARC TNKS2 representativo unido a seis péptidos de sustrato distintos.
- Se deriva una secuencia de consenso de 8 residuos para el reconocimiento de sustrato TNKS común a cuatro ARCs conservados.
- Racionalizó todos los sustratos conocidos de TNKS y explicó las mutaciones de querubinismo en el sustrato 3BP2.
- Se predijeron y validaron objetivos adicionales de TNKS, incluidos Disc1, Striatin, Fat4, RAD54, BCR y MERIT40.
Conclusiones:
- Estableció un consenso basado en reglas para la unión al sustrato de Tankyrase, mejorando la comprensión de la función de TNKS.
- Proporcionó información estructural sobre cómo las enzimas TNKS reconocen y se unen a los sustratos a través de los ARC.
- Los hallazgos ofrecen una base para comprender la patogénesis del querubinismo e identificar nuevos objetivos terapéuticos.
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