Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

RA Saxton, KE Knockenhauer, RL Wolfson… - Science, 2016 - science.org
RA Saxton, KE Knockenhauer, RL Wolfson, L Chantranupong, ME Pacold, T Wang
Science, 2016science.org
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 …
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.
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