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Mecanismos estructurales y bioquímicos de la inhibición de NLRP1 por DPP9

  • 0Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China.
Nature +

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18 de marzo de 2021

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18 de marzo de 2021

Ver abstracta en PubMed

Resumen

Este resumen es generado por máquina.

Las dipeptidilpeptidasas DPP8 y DPP9 suprimen la activación del inflamatorio NLRP1. Los estudios estructurales y bioquímicos revelan que DPP9 forma un complejo con NLRP1, inhibiendo su activación a través de mecanismos de autoinhibición.

Área De La Ciencia

  • Inmunología
  • Biología molecular
  • Biología estructural

Sus Antecedentes

  • El dominio de unión de nucleótidos, los receptores de repetición ricos en leucina (NLR) son mediadores clave de la inmunidad innata a través de la formación de inflamatorios.
  • La activación del inflamatorio NLRP1 depende de la autoclave dentro de su dominio de función para encontrar (FIIND).
  • Se sabe que las dipeptidilpeptidasas DPP8 y DPP9 suprimen la activación de NLRP1, pero el mecanismo no está claro.

Objetivo Del Estudio

  • Elucidar el mecanismo por el cual DPP9 suprime la activación de NLRP1.
  • Investigar las bases estructurales de la interacción entre NLRP1 y DPP9.

Principales Métodos

  • Cristalografía de rayos X para determinar la estructura del complejo NLRP1-DPP9.
  • Ensayos bioquímicos para evaluar la actividad enzimática y de unión.
  • Ensayos funcionales en células humanas para evaluar la inhibición de NLRP1.

Principales Resultados

  • Se identificó un complejo 2: 1 de NLRP1 de rata (rNLRP1) y DPP9 de rata (rDPP9), que contiene un rNLRP1 autoinhibido y un fragmento activo de UPA-CARD.
  • El dominio ZU5 de NLRP1 es crucial para la autoinhibición y el ensamblaje complejo.
  • La unión a DPP9 y la actividad enzimática son necesarias para suprimir la activación de NLRP1 en las células humanas.

Conclusiones

  • DPP9 inhibe la activación del inflamatorio NLRP1 formando un complejo que mejora la autoinhibición.
  • Este estudio revela el mecanismo molecular de la supresión de NLRP1 mediada por DPP9.
  • Los hallazgos proporcionan información sobre la regulación de la activación del inflamatorio NLRP1.

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