Sestrin2 is a leucine sensor for the mTORC1 pathway

Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate...

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Published in:Science (American Association for the Advancement of Science) 2016-01, Vol.351 (6268), p.43-48
Main Authors: Wolfson, Rachel L., Chantranupong, Lynne, Saxton, Robert A., Shen, Kuang, Scaria, Sonia M., Cantor, Jason R., Sabatini, David M.
Format: Article
Language:English
Subjects:
Amino acids
Cell growth
Government regulations
GTPase-Activating Proteins - metabolism
HEK293 Cells
Humans
Kinases
Leucine
Leucine - metabolism
Mechanistic Target of Rapamycin Complex 1
Metabolic Networks and Pathways
Metabolism
Multiprotein Complexes - metabolism
Nuclear Proteins - chemistry
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Pathways
Protein Binding
Proteins
Proteins - chemistry
Proteins - metabolism
Sensors
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
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Summary:Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, a GTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aab2674