Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Abstract
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:
- Publication Date:
- 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)
- OSTI Identifier:
- 1355843
- Alternate Identifier(s):
- OSTI ID: 1345048
- Grant/Contract Number:
- AC02-06CH11357; T32GM007287; S10 RR029205; R01CA103866; AI47389; W81XWH-07- 0448; T32 GM007753; F30 CA189333; DRG-112-12
- Resource Type:
- Published Article
- Journal Name:
- Science
- Additional Journal Information:
- Journal Name: Science Journal Volume: 351 Journal Issue: 6268; Journal ID: ISSN 0036-8075
- Publisher:
- American Association for the Advancement of Science (AAAS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., and Sabatini, D. M. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. United States: N. p., 2015.
Web. doi:10.1126/science.aad2087.
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., & Sabatini, D. M. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. United States. doi:10.1126/science.aad2087.
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., and Sabatini, D. M. Thu .
"Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway". United States. doi:10.1126/science.aad2087.
@article{osti_1355843,
title = {Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway},
author = {Saxton, R. A. and Knockenhauer, K. E. and Wolfson, R. L. and Chantranupong, L. and Pacold, M. E. and Wang, T. and Schwartz, T. U. and Sabatini, D. 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}
}
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DOI: 10.1126/science.aad2087
DOI: 10.1126/science.aad2087
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Works referencing / citing this record:
Optimized E. coli expression strain LOBSTR eliminates common contaminants from His-tag purification : Optimized
journal, August 2013
- Andersen, Kasper R.; Leksa, Nina C.; Schwartz, Thomas U.
- Proteins: Structure, Function, and Bioinformatics, Vol. 81, Issue 11
Basic Local Alignment Search Tool
journal, October 1990
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T-coffee: a novel method for fast and accurate multiple sequence alignment 1 1Edited by J. Thornton
journal, September 2000
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Localization of Rheb to the endomembrane is critical for its signaling function
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Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
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mTOR Signaling in Growth Control and Disease
journal, April 2012
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Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
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- Cell, Vol. 150, Issue 6
Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling
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The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
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Inference of Macromolecular Assemblies from Crystalline State
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Jalview Version 2--a multiple sequence alignment editor and analysis workbench
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X-Ray Diffraction data from Human Sestrin2, Leucine-bound, source of 5DJ4 structure
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