Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human cell lines (crystal structure) |
| Journal | Science |
| Year | 2015 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.aad2087 · PMID 26586190 · Free full text (PMC4698039) |
Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.
| Intervention | Structural (crystal structure of Sestrin2-leucine) |
| Target | Sestrin2 / leucine / GATOR2 / mTORC1 |
| Model | Human cell lines (crystal structure) |
| Effect | Structure of Sestrin2 bound to leucine reveals the leucine-sensing mechanism for the mTORC1 pathway |