Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex.
Science
; 366(6468): 971-977, 2019 11 22.
Article
em En
| MEDLINE
| ID: mdl-31672913
ABSTRACT
The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagAGDPRagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas
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Proteínas Monoméricas de Ligação ao GTP
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Proteínas Supressoras de Tumor
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Lisossomos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos