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La autoinhibición en el transductor de señales CIN85 modula la activación de las células B

Daniel Sieme¹, Michael Engelke², Nasrollah Rezaei-Ghaleh^3,4

¹Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany.

Journal of the American Chemical Society

|December 19, 2023

Resumen

Una interacción intramolecular recientemente descubierta en la proteína CIN85 regula los condensados de señalización de los receptores de células B. Este hallazgo revela cómo la modulación de valencia de CIN85 impacta la activación de las células B y la movilización del calcio.

Área de la Ciencia:

Biología molecular
Señalización celular
La bioquímica

Sus antecedentes:

La señalización del receptor de células B (BCR) se basa en la organización de proteínas dentro de condensados separados por fases.
Las proteínas clave como SLP65 y CIN85 forman estos condensados a través de interacciones entre los dominios de homología Src 3 (SH3) y los motivos ricos en prolina (PRM).
La dinámica conformacional precisa que rige estos condensados y su papel en la señalización de BCR sigue sin estar clara.

Objetivo del estudio:

Investigar las bases estructurales de la formación del condensado SLP65/CIN85.
Identificar nuevas interacciones dentro de CIN85 que regulan su función en la señalización de BCR.
Para aclarar cómo la conformación de proteínas impacta la activación de las células B.

Principales métodos:

Espectroscopia de resonancia magnética nuclear (RMN) de alta resolución para estudiar la conformación de las proteínas.
Análisis de construcciones de proteínas multidominio y regiones de enlace flexibles.
Experimentos de cultivo de células B para evaluar la dinámica de la señalización.

Principales resultados:

Se identificó una interacción intramolecular previamente desconocida entre el dominio C-terminal SH3 (SH3C) de CIN85 y un PRM adyacente.
Se ha demostrado que la fosforilación de un residuo cercano de serina modula dinámicamente esta interacción intramolecular, afectando la valencia de CIN85.
Se confirmó el papel crítico de la interacción en la formación de condensado SLP65/CIN85, el reclutamiento de la membrana CIN85 y la movilización del calcio en las células B.

Conclusiones:

La interacción intramolecular SH3C:PRM en CIN85 es un mecanismo regulador clave.
Esta interacción controla dinámicamente la valencia de CIN85, impactando la formación de condensado y la señalización de las células B.
Los hallazgos proporcionan información sobre la base molecular de la regulación de la transducción de la señal BCR.

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