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Mecanismo de activación del péptido atado de los GPCR de adhesión ADGRG2 y ADGRG4
Peng Xiao1,2,3, Shengchao Guo3, Xin Wen3
1Department of Clinical Laboratory, The Second Hospital, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
Nature
|April 14, 2022
Resumen
Los receptores acoplados a proteínas G de adhesión (aGPCR) se activan a través de una secuencia de Stachel atada, revelada por las estructuras cryo-EM. Este mecanismo informa el diseño de nuevos agonistas y antagonistas de péptidos para estos receptores antiguos.
Área de la Ciencia:
- Biología estructural
- Biología celular molecular
- La bioquímica
Sus antecedentes:
- Los receptores acoplados a proteínas G de adhesión (aGPCR) son antiguos receptores de la superficie celular.
- Los aGPCR a menudo se someten a autoproteólisis, produciendo subunidades alfa y beta.
- El agonismo atado a través de la secuencia de Stachel de la subunidad beta está implicado en la activación de aGPCR.
Objetivo del estudio:
- Para aclarar la base estructural de una activación de GPCR mediada por secuencias de Stachel atadas.
- Investigar la interacción de las secuencias de Stachel con el dominio de siete transmembranas (7TM).
- Proporcionar información para el diseño racional de los agonistas y antagonistas de péptidos dirigidos a la GPCR.
Principales métodos:
- Se determinaron tres estructuras de microscopía criolectrónica (cryo-EM).
- Las estructuras incluyen aGPCRs (ADGRG2, ADGRG4) complejos con el heterotrimero Gs.
- Los complejos incluían secuencias endógenas de Stachel o un agonista de péptidos sintéticos (IP15).
Principales resultados:
- Las estructuras cryo-EM revelan secuencias de Stachel en forma de U profundamente insertadas en los paquetes 7TM.
- El motivo FXφXφXφ de la secuencia de Stachel actúa como "dedos" que median la unión y activación del receptor.
- La estructura de ADGRG2 ((FL) - IP15-Gs explica la afinidad de unión mejorada de IP15 y guía el diseño agonista.
- Se desarrolló un método para generar antagonistas peptídicos mediante la modificación de "residuos de dedos".
Conclusiones:
- Los datos estructurales y bioquímicos proporcionan información clave sobre el mecanismo de activación atado de los aGPCR.
- Los hallazgos facilitan el diseño racional de agonistas y antagonistas basados en péptidos para aGPCR.
- Este trabajo avanza en nuestra comprensión de la señalización de la GPCR y su potencial terapéutico.
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