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Detección molecular de la disociación de adhesión GPCR dependiente de mecano y ligando

Nicole Scholz¹, Anne-Kristin Dahse², Marguerite Kemkemer²

¹Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany. scholzlab@gmail.com.

|March 8, 2023

Resumen

Los receptores acoplados a la proteína G de adhesión (aGPCR) se someten a autoproteólisis, un proceso influenciado por la fuerza mecánica y las interacciones del ligando. Esta disociación permite funciones no celulares autónomas, cruciales para el desarrollo neurológico y que ofrecen posibles objetivos farmacológicos.

Área de la Ciencia:

Biología celular
La neurociencia
La bioquímica

Sus antecedentes:

Los receptores acoplados a la proteína G de adhesión (aGPCR) son similares a las proteínas Notch y se someten a una activación mecano-proteolítica.
Las razones exactas de un procesamiento autoproteolítico de GPCR siguen sin estar claras.
aLos GPCR están implicados en diversas enfermedades, y representan posibles objetivos farmacológicos.

Objetivo del estudio:

Desarrollar un sistema de sensores para la detección de la disociación de un heterodímero GPCR.
Investigar los mecanismos que regulan el procesamiento de la GPCR.
Comprender las funciones fisiológicas de la autoproteólisis aGPCR.

Principales métodos:

Desarrollo de un sensor de liberación de NTF genéticamente codificado para un Drosophila aGPCR (Cirl).
Utilizando el NRS para detectar la disociación del receptor en las neuronas y las células gliales.
Investigando el papel de las interacciones trans- vs. cis con el ligando Tollo en la disociación del receptor.

Principales resultados:

El sensor Cirl-NRS se activa por fuerza mecánica, lo que indica la disociación del receptor.
La disociación del receptor ocurre en las neuronas y las células gliales de la corteza.
La interacción trans entre Cirl y Tollo es necesaria para la liberación de NTF en las células gliales, controlando el tamaño del grupo de neuroblastos.

Conclusiones:

La autoproteólisis de los receptores permite las funciones no autónomas de la célula aGPCR.
aLa disociación de la GPCR está regulada por la expresión del ligando y la fuerza mecánica.
El sistema NRS es una herramienta valiosa para el estudio de los aGPCR y la identificación de objetivos farmacológicos.

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