Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human cells (biochemistry) |
| Journal | Science |
| Year | 2017 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.aao3265 · PMID 29123071 · Free full text (PMC5747364) |
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-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.
| Intervention | Biochemical/genetic (SAMTOR) |
| Target | SAMTOR / GATOR1 / mTORC1 (SAM/methionine) |
| Model | Human cells (biochemistry) |
| Effect | SAMTOR is an S-adenosylmethionine sensor that inhibits mTORC1 by interacting with GATOR1 |