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El Tyr169 evolucionariamente conservado estabiliza el bucle β2-α2 de la proteína priónica

Danzhi Huang¹, Amedeo Caflisch

¹Department of Biochemistry University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Journal of the American Chemical Society

|February 12, 2015

Resumen

La estructura de lazo β2-α2 de la proteína priónica es clave para su conversión. Una mutación específica (Y169G) reduce la barrera de energía para esta transición de bucle, lo que afecta la agregación de priones.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
La dinámica molecular es la dinámica molecular.

Sus antecedentes:

Las proteínas priónicas de mamíferos (PrP) existen en forma celular (PrP(C)) y en formas agregadas y mal plegadas.
La región del bucle β2-α2 (residuos 165-175) está implicada en el proceso de conversión.
Comprender la dinámica del bucle es crucial para los mecanismos de la enfermedad priónica.

Objetivo del estudio:

Para investigar la transición estructural del bucle β2-α2 de la proteína priónica.
Para determinar el paisaje energético de la transición del bucle en proteínas priónicas de tipo salvaje y mutantes.
Para aclarar el papel de la tirosina 169 en la estabilización de la conformación de la proteína priónica nativa.

Principales métodos:

Simulaciones de dinámica molecular imparcial de una proteína priónica mutante de punto único Y169G.
Muestreo de superficie de energía libre utilizando múltiples conformaciones de simulaciones.
Determinación de los perfiles de energía libre utilizando dos métodos computacionales distintos.

Principales resultados:

La mutación Y169G reduce significativamente la barrera de energía para la transición del bucle β2-α2 de un giro helicoidal 310 a un giro β en aproximadamente 2,5 kcal/mol.
El apilamiento favorable de anillos aromáticos entre Y169 y F175, y un enlace de hidrógeno estable entre Y169 y D178 estabilizan la conformación helicoidal tipo 310 salvaje.
La transición del bucle a un giro β expone una región hidrofóbica (residuos 169-YSNQNNF-175) al solvente.

Conclusiones:

La tirosina conservada en el residuo 169 (Y169) juega un papel crítico en la estabilización del giro helicoidal de 310 dentro del bucle β2-α2 de las proteínas priónicas de mamíferos.
Esta estabilización por Y169 impide activamente la transición del bucle a un giro β, evitando así la adopción de una conformación propensa a la agregación.
Los hallazgos proporcionan información molecular sobre los determinantes estructurales de la conversión y agregación de proteínas priónicas.

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