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Enlace mecánico entre la dimerización de PKR, la autofosforilación y el reconocimiento del sustrato eIF2alfa.

Madhusudan Dey¹, Chune Cao, Arvin C Dar

¹Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

|September 24, 2005

Resumen

Este resumen es generado por máquina.

La proteína quinasa PKR es una proteína

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Área de la Ciencia:

Biología Molecular Biología Molecular
Virología Virología.
La bioquímica es la bioquímica.

Sus antecedentes:

La proteína quinasa PKR es una proteína antiviral clave que inhibe la síntesis de proteínas.
La activación de PKR se desencadena por la unión de ARN de doble cadena, lo que lleva a la dimerización y la autofosforilación.
La fosforilación del factor de iniciación de la traducción eIF2alfa por PKR detiene la síntesis de proteínas.

Objetivo del estudio:

Identificar las mutaciones que activan la PKR independientemente de sus dominios reguladores.
Para aclarar el papel del dominio catalítico de la quinasa en la activación de PKR y el reconocimiento de sustratos.
Para definir el mecanismo de activación de PKR y su interacción con eIF2alpha.

Principales métodos:

Mutagenesis dirigida al sitio para generar variantes de PKR.
Ensayos de kinasa in vitro para medir la autofosforilación y la eIF2alfa fosforilación.
Análisis de mutaciones dentro del dominio catalítico de PKR y residuos conservados.

Principales resultados:

Las mutaciones que activan la PKR se asignaron a una superficie de dimerización en el dominio catalítico.
Las mutaciones específicas en esta superficie inhiben la autofosforilación de PKR y la fosforilación eIF2alfa.
La mutación de Thr446 alteró la fosforilación eIF2alfa y la unión al pseudo-substrato viral.
Helix alphaG dentro del dominio catalítico fue identificado como crucial para el reconocimiento de eIF2alpha.

Conclusiones:

La dimerización del dominio catalítico es un paso crítico en la activación ordenada de PKR.
La autofosforilación de Thr446 y la unión específica al sustrato eIF2alfa son eventos aguas abajo.
Los hallazgos proporcionan información sobre el mecanismo molecular de la actividad antiviral de PKR.