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La selección conformacional guía el reclutamiento de β-arrestina en un receptor acoplado a proteínas G sesgado

Andrew B Kleist^1,2, Shawn Jenjak¹, Andrija Sente³

¹Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Science (New York, N.Y.)

|July 20, 2022

Resumen

Los receptores acoplados a proteínas G (GPCR) como los receptores quimioquinos atípicos (ACKR) reclutan β-arrestinas. Este estudio revela que la dinámica conformacional en ACKR3 es clave para la unión a la β-arrestina, ofreciendo información sobre la señalización sesgada de GPCR.

Área de la Ciencia:

La bioquímica
Biología estructural
Farmacología

Sus antecedentes:

Los receptores acoplados a proteínas G (GPCR) son proteínas de señalización celular cruciales.
Las β-arrestinas median diversas funciones celulares aguas abajo de los GPCR.
Los receptores atípicos de quimiocinas (ACKR) son GPCR sesgados que reclutan las β-arrestinas pero no las proteínas G.

Objetivo del estudio:

Investigar la dinámica estructural subyacente al reclutamiento de la β-arrestina en el ACKR3.
Para aclarar el mecanismo de la señalización sesgada en ACKR3.

Principales métodos:

Espectroscopia de Resonancia Magnética Nuclear (RMN) en el ¹³CH₃-ε-metionina-marcado por ACKR3.
Análisis de los mutantes ACKR3 defectuosos en el reclutamiento de la β-arrestina.

Principales resultados:

El reclutamiento de β-arrestina en ACKR3 está relacionado con el intercambio conformacional en las regiones de bolsillo de unión de ligando y β-arrestina.
Un centro alostérico en el núcleo del receptor regula los estados conformacionales.
La dinámica de los receptores se sintoniza en las regiones intracelulares y extracelulares durante el reclutamiento de la β-arrestina.

Conclusiones:

La selección conformacional es un mecanismo clave que guía el reclutamiento de la β-arrestina a ACKR3.
La comprensión de la dinámica de ACKR3 proporciona información sobre las vías de señalización de GPCR sesgadas.

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