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La unión simultánea de las señales de orientación NET1 y RGM bloquea la señalización NEO1 extracelular

Ross A Robinson¹, Samuel C Griffiths¹, Lieke L van de Haar²

¹Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

|March 19, 2021

Resumen

Neogenin (NEO1) integra las señales opuestas de Netrin-1 (NET1) y los ligandos de la molécula de guía repulsiva (RGM) formando un complejo ternario. Este súper ensamblaje silencia la señalización aguas abajo, previniendo el colapso del cono de crecimiento celular y regulando la migración de las neuronas.

Área de la Ciencia:

Biología molecular
La neurociencia
Biología celular

Sus antecedentes:

Los receptores de superficie celular integran diversas señales extracelulares durante procesos cruciales como la migración y la diferenciación.
La neogenina (NEO1) exhibe una doble funcionalidad, mediando la atracción a través de Netrin-1 (NET1) y la repulsión a través de los ligandos de la molécula de guía repulsiva (RGM).

Objetivo del estudio:

Esclarecer el mecanismo de integración de la señal cuando NEO1 se une simultáneamente a los ligandos con funciones opuestas.
Para determinar la base estructural de cómo NEO1 concilia señales atractivas y repulsivas.

Principales métodos:

Cristalografía de rayos X para determinar la estructura del complejo NEO1-NET1-RGM.
Pruebas bioquímicas para evaluar la transmisión de señales.
Ensayos basados en células para evaluar el colapso del cono de crecimiento y la migración de neuronas.

Principales resultados:

Se forma un complejo ternario de NEO1, NET1 y RGM, creando un superconjunto "trimero de trimeros" en la membrana celular.
Este superconjunto inhibe el colapso del cono de crecimiento mediado por RGMA- NEO1 y la migración de neuronas mediada por RGMA/ NET1- NEO1.
La formación de complejos competentes para la señalización y el agrupamiento del ectodominio NEO1 son evitados por el superconjunto.

Conclusiones:

La unión simultánea del ligando a un solo receptor no siempre resulta en una señalización competitiva.
Una formación supercompleja de orden superior puede conducir al silenciamiento recíproco de salidas funcionales opuestas.
Este mecanismo proporciona información sobre cómo las células integran señales extracelulares complejas para respuestas celulares precisas.

Palabras clave:

Neogenina y sus derivados Netrin y sus derivados Regeneración de los axones Migración celular receptores de la superficie celular estructura compleja Señalización de los morfógenos Interacciones proteína-proteína molécula de guía repulsiva Transducción de señales

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