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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

Saxton, Robert A., Knockenhauer, Kevin E., Wolfson, Rachel L., Chantranupong, Lynne, Pacold, Michael E., Wang, Tim, Schwartz, Thomas U., and Sabatini, David M.. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. United States: N. p., Web. doi:10.1126/science.aad2087.
Saxton, Robert A., Knockenhauer, Kevin E., Wolfson, Rachel L., Chantranupong, Lynne, Pacold, Michael E., Wang, Tim, Schwartz, Thomas U., & Sabatini, David M.. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. United States. doi:10.1126/science.aad2087.
Saxton, Robert A., Knockenhauer, Kevin E., Wolfson, Rachel L., Chantranupong, Lynne, Pacold, Michael E., Wang, Tim, Schwartz, Thomas U., and Sabatini, David M.. 2015. "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway". United States. doi:10.1126/science.aad2087. https://www.osti.gov/servlets/purl/1345048.
@article{osti_1345048,
title = {Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway},
author = {Saxton, Robert A. and Knockenhauer, Kevin E. and Wolfson, Rachel L. and Chantranupong, Lynne and Pacold, Michael E. and Wang, Tim and Schwartz, Thomas U. and Sabatini, David M.},
abstractNote = {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.},
doi = {10.1126/science.aad2087},
journal = {Science},
number = 6268,
volume = 351,
place = {United States},
year = {2015},
month = {11}
}

Works referenced in this record:

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925