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Más allá del núcleo amiloide: modulación de la diversidad conformal agregada por mutaciones en las regiones no

Mingrui Chen¹, Zhongyi Jian¹, Mingzhan Wang²

¹State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.

Journal of the American Chemical Society

|September 4, 2025

Resumen

Las secuencias de flanqueo en las proteínas amiloides alteran significativamente las estructuras e interacciones de los agregados de la hoja β. Estas mutaciones revelan procesos de remodelación deterministas, que ofrecen información sobre la agregación de proteínas y posibles estrategias terapéuticas para las amiloidopatías.

Área de la Ciencia:

La bioquímica
Biología estructural
Biofísica molecular

Sus antecedentes:

Las regiones no amiloidogénicas juegan un papel crucial en la regulación de la agregación y la citotoxicidad de las proteínas amiloidales.
Los mecanismos precisos por los cuales estas secuencias de flanqueo ejercen control siguen siendo en gran medida indefinidos.

Objetivo del estudio:

Investigar cómo las secuencias de flanqueo modulan la heterogeneidad conformacional en el segmento amiloide p53 238-262.
Para aclarar los cambios estructurales e interaccionales inducidos por mutaciones en regiones no centrales de proteínas amiloidales.

Principales métodos:

Se utilizó microscopía de túnel de barrido (STM) para analizar el segmento amiloide p53 238-262.
Se compararon secuencias de tipo salvaje con tres mutaciones patógenas (R248W, R248Q, R249S) en regiones flanqueantes.

Principales resultados:

Se encontraron alteraciones de flanqueo para remodelar los agregados de la hoja β, induciendo plasticidad conformacional en conjuntos de hebra β.
Las mutaciones generaron nuevos subestados conformacionales y eliminaron los existentes, lo que condujo a diversas redes de interacción intermolecular.
El mapeo cuantitativo reveló una diversificación significativa de las interacciones entre cadenas β y patrones de interacción dominantes alterados.

Conclusiones:

Las mutaciones flanqueantes inducen una remodelación conformacional determinista en los agregados de hojas β a través de reordenamientos estructurales no estocásticos.
Estos hallazgos mejoran la comprensión mecanicista del control de la secuencia no central en la agregación de proteínas.
Se han identificado objetivos terapéuticos potenciales para la modulación del ensamblaje de la hoja β en amiloidopatías.

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