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Title: Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Eukaryotic cells coordinate growth with the availability of nutrients through mTOR complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag GTPases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. We present the 2.7-Å 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. Lastly, these results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1]
  1. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States); Whitehead Institute for Biomedical Research, Cambridge, MA (United States); Koch Institute for Integrative Center Research, Cambridge, MA (United States)
  2. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357; T32GM007287; S10 RR029205; R01CA103866; AI47389; W81XWH-07- 0448; T32 GM007753; F30 CA189333; DRG-112-12
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 351; Journal Issue: 6268; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); US Dept. of Defense (DOD)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1345048