Details

Autor(en) / Beteiligte

• Saxton, Robert A.
• Knockenhauer, Kevin E.
• Wolfson, Rachel L.
• Chantranupong, Lynne
• Pacold, Michael E.
• Wang, Tim
• Schwartz, Thomas U.
• Sabatini, David M.

Titel

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Ist Teil von

• Science (American Association for the Advancement of Science), 2016-01, Vol.351 (6268), p.53-58

Ort / Verlag

United States: American Association for the Advancement of Science

Erscheinungsjahr

2016

Link zum Volltext

Quelle

American Association for the Advancement of Science

Beschreibungen/Notizen

• 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.