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La separación de fase de los mutantes SHP2 asociados a la enfermedad subyace a la hiperactivación de MAPK

  • 0Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
Cell +

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1 de octubre de 2020

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1 de octubre de 2020

Ver abstracta en PubMed

Resumen

Este resumen es generado por máquina.

Las mutaciones SHP2 asociadas a la enfermedad causan trastornos del desarrollo al promover la separación de fase líquido-líquido (LLPS). La inhibición de SHP2 LLPS restaura la actividad de la proteína tirosina fosfatasa (PTP) y puede ofrecer estrategias terapéuticas para estas afecciones.

Área De La Ciencia

  • La bioquímica
  • Biología molecular
  • La genética

Sus Antecedentes

  • SHP2 (PTPN11) es una proteína tirosina fosfatasa no receptora crucial para la señalización RAS-MAPK en el desarrollo.
  • Las mutaciones activadoras e inactivadoras de PTPN11 causan trastornos de desarrollo superpuestos, una paradoja inexplicable por la actividad enzimática sola.

Objetivo Del Estudio

  • Investigar el papel de la separación de fase líquido-líquido (LLPS) en los trastornos del desarrollo asociados con SHP2.
  • Determinar si el LLPS es un mecanismo común para los mutantes SHP2 asociados a la enfermedad.
  • Explorar el objetivo terapéutico de SHP2 LLPS.

Principales Métodos

  • Análisis del comportamiento del mutante SHP2 utilizando ensayos LLPS.
  • Investigó el papel del dominio PTP en SHP2 LLPS.
  • Se evaluó el impacto de los inhibidores alostéricos en la SHP2 y su actividad.
  • Estudió la interacción entre el SHP2 mutante y el tipo salvaje dentro de los condensados de LLPS.

Principales Resultados

  • Los mutantes SHP2 asociados a la enfermedad exhiben un comportamiento LLPS común mediado por el dominio PTP.
  • SHP2 LLPS está regulado por un mecanismo autoinhibidor y puede ser atenuado por inhibidores alostéricos, aumentando la actividad de PTP.
  • El SHP2 mutante en LLPS puede reclutar y activar el SHP2 de tipo salvaje, promoviendo la señalización MAPK.

Conclusiones

  • LLPS actúa como un mecanismo de ganancia de función en enfermedades humanas relacionadas con SHP2.
  • El LLPS es un nuevo mecanismo de regulación de las proteínas tirosina fosfatasas (PTP).
  • Dirigirse a SHP2 LLPS presenta una estrategia terapéutica potencial para los trastornos del desarrollo.

Palabras clave:

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