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

Science
Authors
Keywords
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.

Year of Publication
2016
Journal
Science
Volume
351
Issue
6268
Pages
53-8
Date Published
2016 Jan 01
ISSN
1095-9203
URL
DOI
10.1126/science.aad2087
PubMed ID
26586190
PubMed Central ID
PMC4698039
Links
Grant list
R01 AI047389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
P41 GM103403 / GM / NIGMS NIH HHS / United States
F30 CA189333 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
F31 CA180271 / CA / NCI NIH HHS / United States
T32GM007287 / GM / NIGMS NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
R01CA103866 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
F31 CA189437 / CA / NCI NIH HHS / United States
S10 RR029205 / RR / NCRR NIH HHS / United States
AI47389 / AI / NIAID NIH HHS / United States