Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
| Autor: | Roberto Zoncu, David M. Sabatini, Liron Bar-Peled, Lawrence D. Schweitzer |
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| Rok vydání: | 2012 |
| Předmět: |
Molecular Sequence Data
GTPase Guanosine triphosphate Biology Mechanistic Target of Rapamycin Complex 1 General Biochemistry Genetics and Molecular Biology Article GTP Phosphohydrolases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Guanine Nucleotide Exchange Factors Humans Nucleotide Amino Acid Sequence Amino Acids Peptide sequence 030304 developmental biology Adaptor Proteins Signal Transducing chemistry.chemical_classification 0303 health sciences Biochemistry Genetics and Molecular Biology(all) TOR Serine-Threonine Kinases Signal transducing adaptor protein Proteins Ragulator complex Amino acid HEK293 Cells chemistry Biochemistry 030220 oncology & carcinogenesis Multiprotein Complexes Drosophila Guanine nucleotide exchange factor biological phenomena cell phenomena and immunity Signal Transduction |
| Zdroj: | Cell. 150(6):1196-1208 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2012.07.032 |
| Popis: | The mTOR Complex 1 (mTORC1) pathway promotes cell growth in response to a diverse set of cues, including growth factors as well as energy and amino acid levels. Amino acids signal through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. The four mammalian Rag proteins form obligate heterodimers consisting of RagA or RagB bound to RagC or RagD. A key upstream component of the Rag GTPases is Ragulator, a trimeric complex that tethers them to the lysosome and also interacts with the v-ATPase, which is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of GTP to RagB, a critical step in the sensing mechanism, but the factors that regulate Rag nucleotide loading are unknown. Here, we identify the proteins encoded by the HBXIP and C7orf59 genes as novel Ragulator components that are required for mTORC1 activation by amino acids. The pentameric Ragulator has nucleotide exchange activity towards RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by revealing Ragulator to be a scaffold with guanine nucleotide exchange factor (GEF) activity for the Rag GTPases. |
| Databáze: | OpenAIRE |
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