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Resolviendo la paradoja de unión de heterodímero NFκB: la tensión y la frustración guían la unión de factores de

Davit A Potoyan^1,2, Carlos Bueno², Weihua Zheng²

¹Department of Chemistry, Iowa State University , Ames, Iowa 50011, United States.

Journal of the American Chemical Society

|November 30, 2017

Resumen

La familia NFκB

Área de la Ciencia:

Biología molecular
La biofísica
La genómica

Sus antecedentes:

Los factores de transcripción eucariotas a menudo funcionan como oligómeros, influyendo en la regulación de los genes.
La familia del factor nuclear kappa B (NFκB) comprende los factores de transcripción clave involucrados en los procesos celulares.
Los dimeros NFκB exhiben diferentes afinidades de unión al ADN y funciones reguladoras.

Objetivo del estudio:

Investigar la base molecular de las afinidades de unión al ADN diferencial entre los dimeros NFκB.
Aclarar los factores estructurales y energéticos que rigen los mecanismos de unión y desvinculación de los homo- y heterodímeros de NFκB.
Comprender cómo la arquitectura de las proteínas dicta la función del factor de transcripción en la regulación de los genes.

Principales métodos:

Análisis computacional utilizando herramientas de paisaje energético.
Simulaciones que emplean un paisaje de energía predictivo hamiltoniano.
Extracción de los componentes principales a partir de las fluctuaciones de las coordenadas cartesianas y los contactos físicos.

Principales resultados:

Los heterodímeros de NFκB p65p50 exhiben una unión más fuerte al ADN que los homodímeros de p50p50 y p65p65.
La frustración en la interfaz heterodimérica mejora la plasticidad conformacional para una mejor acomodación del ADN.
La energía elástica y la tensión mecánica en los dímeros NFκB son cuantificables e influyen en la dinámica de unión/desunión.

Conclusiones:

La arquitectura molecular, específicamente la frustración de la interfaz, dicta la afinidad de unión del ADN del dímero NFκB.
La plasticidad conformacional y las propiedades mecánicas son determinantes clave de las interacciones entre el factor de transcripción y el ADN.
La comprensión de estas contribuciones energéticas proporciona información sobre la regulación genética precisa por los dímeros NFκB.

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