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La activación alostérica de la PDZ Par-6 a través de una transición de despliegue parcial
Dustin S Whitney1, Francis C Peterson, Evgenii L Kovrigin
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Journal of the American Chemical Society
|May 28, 2013
Resumen
La flexibilidad de la proteína 6 (Par-6) defectuosa en la partición es crucial para su función. Inesperadamente, el despliegue parcial del dominio PDZ facilita la regulación alostérica, revelando un nuevo mecanismo para la dinámica de las proteínas.
Área de la Ciencia:
- La bioquímica de las proteínas.
- Biología molecular La biología molecular.
- Biología estructural Biología estructural.
Sus antecedentes:
- Las proteínas equilibran los estados nativos y desplegados para la función, a veces sacrificando la estabilidad por la flexibilidad.
- La proteína 6 (Par-6) defectuosa en la partición regula el complejo de polaridad Par a través de su módulo de unión de interacción Cdc42/Rac PSD-95/Dlg/ZO-1 (CRIB-PDZ).
- La regulación alostérica en Par-6 implica reordenamientos en la interfaz CRIB:PDZ, que afectan a la unión del ligando de la PDZ.
Objetivo del estudio:
- Para investigar la dinámica y la estabilidad termodinámica del dominio Par-6 PDZ durante la regulación alostérica.
- Para aclarar los mecanismos estructurales subyacentes al intercambio de la cadena lateral L164/K165 en la Parte-6.
- Explorar el papel del despliegue de proteínas en el mecanismo alostérico de Par-6.
Principales métodos:
- Mediciones de dinámica en escalas de tiempo de microsegundos a milisegundos.
- Análisis de la estabilidad estructural local dentro del dominio de la PDZ.
- Evaluaciones de la estabilidad termodinámica del dominio de la PDZ.
Principales resultados:
- El intercambio de la cadena lateral L164/K165 en Par-6 requiere un reordenamiento estructural más grande de lo previsto.
- El dominio PDZ exhibe una estabilidad termodinámica modesta (∼3 kcal/mol), reducida aún más por las interacciones del dominio CRIB.
- El despliegue parcial del dominio PDZ interrumpe los contactos terciarios, lo que permite el interruptor L / K crucial para la activación alostérica.
Conclusiones:
- El despliegue parcial del estado nativo es un componente integral del mecanismo alostérico Par-6.
- Este hallazgo sugiere que el despliegue del estado nativo puede ser un mecanismo general para la regulación funcional en otras proteínas marginalmente estables.
- La flexibilidad de las proteínas esencial para la catálisis y la unión se puede lograr a través de eventos controlados de despliegue parcial.
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