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Las proteínas CASTOR son sensores de arginina para la vía mTORC1

Lynne Chantranupong¹, Sonia M Scaria¹, Robert A Saxton¹

¹Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 415 Main Street, Cambridge MA 02142, USA.

|March 15, 2016

Resumen

CASTOR1 actúa como un nuevo sensor de arginina, interactuando con GATOR2 para regular la vía mTORC1. Este descubrimiento aclara cómo la privación de arginina inhibe la señalización del crecimiento celular.

Área de la Ciencia:

Señales celulares
Biología molecular
La bioquímica

Sus antecedentes:

Los aminoácidos regulan la vía del complejo mTOR I (mTORC1) a través de las Rag GTPasas.
Los complejos GATOR1 (GAP) y GATOR2 modulan la actividad de la Rag GTPasa.
El mecanismo preciso de detección de arginina para la activación y la represión de mTORC1 sigue sin estar claro.

Objetivo del estudio:

Identificar los componentes moleculares involucrados en la detección de arginina para la regulación de mTORC1.
Para aclarar el mecanismo por el cual la privación de arginina inhibe mTORC1.
Para caracterizar la función de la proteína no caracterizada CASTOR1.

Principales métodos:

Estudios de interacción proteína-proteína para evaluar la formación del complejo CASTOR1-GATOR2.
Ensayos bioquímicos para determinar la afinidad de unión a la arginina de CASTOR1.
Experimentos celulares para evaluar el papel de CASTOR1 en la señalización de mTORC1 bajo diferentes condiciones de arginina.

Principales resultados:

CASTOR1 interactúa con GATOR2 y es esencial para la inhibición de mTORC1 mediada por la privación de arginina.
CASTOR1 homodimeriza y puede heterodimerizar con CASTOR2.
La unión de la arginina a CASTOR1 interrumpe el complejo CASTOR1- GATOR2, con una constante de disociación de aproximadamente 30 μM, que es crucial para la activación de mTORC1.

Conclusiones:

CASTOR1 funciona como un sensor de arginina directo para la vía mTORC1.
CASTOR1 integra las señales de disponibilidad de arginina para modular la actividad de mTORC1.
Estos hallazgos revelan un nuevo mecanismo para la detección de nutrientes en el control del crecimiento celular.

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