Unknown

Dataset Information

0

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.


ABSTRACT: 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.

SUBMITTER: Saxton RA 

PROVIDER: S-EPMC4698039 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.

Saxton Robert A RA   Knockenhauer Kevin E KE   Wolfson Rachel L RL   Chantranupong Lynne L   Pacold Michael E ME   Wang Tim T   Schwartz Thomas U TU   Sabatini David M DM  

Science (New York, N.Y.) 20151119 6268


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 c  ...[more]

Similar Datasets

| S-EPMC4698017 | biostudies-literature
| S-EPMC4899281 | biostudies-literature
| S-EPMC6003318 | biostudies-literature
| S-EPMC4377584 | biostudies-literature
| S-EPMC5187391 | biostudies-literature
| S-EPMC4402725 | biostudies-literature
| S-EPMC3403464 | biostudies-literature
| S-EPMC3199488 | biostudies-literature
| S-EPMC5087270 | biostudies-literature
| S-EPMC4691887 | biostudies-literature