Sestrin2 is a leucine sensor for the mTORC1 pathway

By Rachel L. Wolfson, Lynne Chantranupong, R. A. Saxton, K. Shen, Sonia M. Scaria, J. Cantor, David M. Sabatini. Science, 2015

1,154 citations recorded by the source corpus.

From sensing leucine to metabolic control The mTORC1 protein kinase complex plays central roles in regulating cell growth and metabolism and is implicated in common human diseases such as diabetes and cancer. The level of the amino acid leucine tells an organism a lot about its physiological state, including how much food is available, how much insulin is going to be needed, and whether new muscle mass can be made (see the Perspective by Buel and Blenis). Wolfson et al. identified a biochemical sensor of leucine, Sestrin2, which connects the concentration of leucine to the control of organismal metabolism and growth. When leucine bound to Sestrin2, it was released from a complex with the mTORC1 regulatory factor GATOR2, activating the mTORC1 complex. Saxton et al. describe the crystal structure of Sestrin2 and show how it specifically detects leucine. Aylett et al. determined the structure of human mTORC1 by cryoelectron microscopy and the crystal structure of a regulatory subunit, Raptor. The results reveal the structural basis for the function and intricate regulation of this important enzyme, which is also a strategic drug target. Science, this issue p. 43, p. 48, p. 53; see also p. 25 A protein that senses leucine concentration for metabolic control is identified. [Also see Perspective by Buel and Blenis] 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, aGTPase-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.

Subfields: Molecular Biology

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Citations in the corpus

Metabolic Control of Longevity. (2016, background): “Interestingly, Sesn2 is a leucine sensor for the MTORC1 pathway, connecting the availability of this amino acid to the control of organismal growth (Wolfson et al., 2016).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
A systems study reveals concurrent activation of AMPK and mTOR by amino acids (2016, background): “Here, the branched-chain aa leucine, as well as glutamine and arginine deserve particular attention, as they all have been identiﬁed as being important in the regulation of the mTOR network 5,62,63 .”
Nutrient sensing and TOR signaling in yeast and mammals (2017, neutral): “Upon leucine binding, SESTRIN2 dissociates from GATOR2, which results in mTORC1 translocation to the lysosome (Wolfson et al , 2016).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Both D. melanogaster and C. elegans do have a Sestrin homolog, however, and dmSestrin also binds leucine (Wolfson et al., 2016).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “elegans do have a Sestrin homolog however, and dmSestrin also binds leucine (Wolfson et al., 2016).”
Branched Chain Amino Acids: Beyond Nutrition Metabolism (2018, background): “Leu depletion directly caused the Sestrin2-GATOR2 interaction, and Leu must be able to bind Sestrin2 before activating mTORC1 in cells [60].”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “For experiments that required leucine, arginine or amino acid starvation or restimulation, cells were treated as previously described (Wolfson et al., 2015).”