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Cambio de conformación de la proteína priónica celular después de la separación de la fase líquido-líquido regulada

Yangyi Liu^1,2, Marcus D Tuttle¹, Mikhail A Kostylev²

¹Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States.

Journal of the American Chemical Society

|September 26, 2024

Resumen

La separación de fase líquido-líquido (LLPS) de la proteína priónica (PrP^C) implica un proceso de maduración. Este cambio conformacional, acelerado por mutaciones y PSCMA, puede conducir a la neurodegeneración.

Área de la Ciencia:

La bioquímica
La neurociencia
Biología molecular

Sus antecedentes:

La separación de fase líquido-líquido (LLPS) de proteínas intrínsecamente desordenadas está relacionada con enfermedades neurodegenerativas.
Los mecanismos precisos por los que el LLPS contribuye a la neurodegeneración siguen sin estar claros.
La proteína priónica celular (PrP) está implicada en trastornos neurodegenerativos.

Objetivo del estudio:

Para investigar el proceso de maduración de PrP^C después de LLPS.
Explorar las funciones reguladoras de las mutaciones y el ácido poliestirenesulfónico-acido co-maleico (PSCMA) en la PrP^C y la maduración.
Para aclarar el papel potencial de los cambios conformacionales de PrP^C después de LLPS en la neurodegeneración.

Principales métodos:

Inducción de la separación de fase líquido-líquido PrP^C mediante el uso de PSCMA.
Espectroscopia de resonancia magnética nuclear (RMN) para detectar los estados conformacionales.
Análisis de la cinética de maduración de PrP^C y la dinámica molecular.

Principales resultados:

El PSCMA induce la LLPS reentrante de PrP, reduciendo su concentración de saturación (C) en 100 veces.
PrP^C se somete a un proceso de maduración, pasando a un estado más sólido con movimiento molecular restringido, independientemente del método de inducción.
La mutación E200K asociada con las enfermedades priónicas acelera la maduración de PrP^C.
El LLPS inducido por PSCMA estabiliza un estado conformacional intermedio, mientras que el estado final rico en hojas β es consistente en todas las condiciones.

Conclusiones:

PrP^C se somete a una maduración conformacional después de LLPS, pasando a un estado más rígido.
Este cambio conformacional posterior a LLPS y la dinámica alterada representan un mecanismo potencial para la neurodegeneración inducida por LLPS.
El PSCMA modula el PrP^C y el LLPS y la maduración, ofreciendo información sobre estrategias terapéuticas para priones y enfermedades relacionadas.

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