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Un mecanismo molecular para la señalización específica del ligando Wnt
Marie Eubelen1, Naguissa Bostaille1, Pauline Cabochette1
1Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies B-6041, Belgium.
Science (New York, N.Y.)
|July 21, 2018
Resumen
Las células responden selectivamente a los ligandos Wnt a través de un nuevo mecanismo que involucra a las proteínas Gpr124 y Reck. Este proceso mejora la especificidad de la señalización Wnt7, ofreciendo información sobre la regulación de la vía Wnt.
Área de la Ciencia:
- Biología celular
- Biología molecular
- Biología del desarrollo
Sus antecedentes:
- Las vías de señalización WNT regulan procesos celulares cruciales.
- Las células exhiben respuestas selectivas a diferentes ligandos Wnt, un fenómeno que no se explica completamente por las interacciones Wnt/Frizzled.
- Las células endoteliales del cerebro muestran respuestas específicas a Wnt7, mediadas por Gpr124 y Reck.
Objetivo del estudio:
- Elucidar los mecanismos moleculares subyacentes al reconocimiento selectivo del ligando Wnt.
- Para entender cómo Gpr124 y Reck facilitan la especificidad de Wnt7 en las células endoteliales del cerebro.
- Investigar las bases estructurales de la diversificación funcional de los miembros de la familia Wnt.
Principales métodos:
- Ensayos bioquímicos para determinar las afinidades de unión entre Wnt7 y Reck.
- Estudios sobre la interacción entre Gpr124 y Dishevelled.
- Análisis de la formación del signaloso y la dinámica del complejo Wnt/Frizzled/Lrp5/6.
- Investigando el papel de la polimerización de proteínas en la amplificación de la señal Wnt.
Principales resultados:
- La proteína Reck se une a la región de enlace desordenada de Wnt7 con baja afinidad micromolar.
- La interacción Gpr124-Dishevelled es crítica para la presentación de Wnt7 ligado a Reck a los receptores Frizzled.
- La polimerización desgarrada impulsa la formación de Wnt/Frizzled/Lrp5/6 señalosomas dinámicos.
- Estos señalosomas aumentan las concentraciones locales de Wnt7, mejorando la especificidad de señalización de Frizzled.
Conclusiones:
- Se describe un nuevo mecanismo para la decodificación del ligando Wnt por las células de los vertebrados.
- La interacción entre Gpr124, Reck y Dishevelled dicta la especificidad de señalización de Wnt7.
- Se proporcionan conocimientos estructurales y mecanicistas sobre la diversificación funcional de Wnt.
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