Sestrin2 is a direct leucine sensor whose leucine binding releases GATOR2 to activate mTORC1.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2015 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.aab2674 · PMID 26449471 · Free full text (PMC4698017) |
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.
| Intervention | Biochemical/genetic (Sestrin2) |
| Target | Sestrin2 / GATOR2 / Rag / mTORC1 |
| Model | Mammalian cells |
| Effect | Sestrin2 is a leucine sensor for mTORC1; leucine (not arginine) binding relieves Sestrin2 inhibition |