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SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway

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Science  10 Nov 2017:
Vol. 358, Issue 6364, pp. 813-818
DOI: 10.1126/science.aao3265

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SAMTOR joins the family

The amino acid methionine is widely appreciated to have interesting effects on animal physiology. Diets low in methionine increase longevity and overall health, particularly glucose homeostasis. Gu et al. describe a potential molecular link between the effects of methionine restriction and the growth controller mTOR complex 1 (mTORC1), a well-validated regulator of life span and health span in many organisms. They identify a protein that they named SAMTOR as a component of the nutrient-sensing pathway upstream of mTORC1. SAMTOR directly binds S-adenosylmethionine (SAM), a metabolite made from methionine, and is necessary for regulating mTORC1 in response to methionine.

Science, this issue p. 813

Abstract

mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

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