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); 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}
}
DOI: 10.1126/science.aad2087
Web of Science
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Works referencing / citing this record:
Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes
journal, May 2000
- Lynch, Christopher J.; Fox, Heather L.; Vary, Thomas C.
- Journal of Cellular Biochemistry, Vol. 77, Issue 2
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.
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Basic Local Alignment Search Tool
journal, October 1990
- Altschul, S.
- Journal of Molecular Biology, Vol. 215, Issue 3
T-coffee: a novel method for fast and accurate multiple sequence alignment 1 1Edited by J. Thornton
journal, September 2000
- Notredame, Cédric; Higgins, Desmond G.; Heringa, Jaap
- Journal of Molecular Biology, Vol. 302, Issue 1
Localization of Rheb to the endomembrane is critical for its signaling function
journal, June 2006
- Buerger, Claudia; DeVries, Ben; Stambolic, Vuk
- Biochemical and Biophysical Research Communications, Vol. 344, Issue 3
Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
journal, April 2010
- Sancak, Yasemin; Bar-Peled, Liron; Zoncu, Roberto
- Cell, Vol. 141, Issue 2
mTOR Signaling in Growth Control and Disease
journal, April 2012
- Laplante, Mathieu; Sabatini, David M.
- Cell, Vol. 149, Issue 2
Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
journal, September 2012
- Bar-Peled, Liron; Schweitzer, Lawrence D.; Zoncu, Roberto
- Cell, Vol. 150, Issue 6
Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling
journal, September 2014
- Peng, Min; Yin, Na; Li, Ming O.
- Cell, Vol. 159, Issue 1
The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
journal, October 2014
- Chantranupong, Lynne; Wolfson, Rachel L.; Orozco, Jose M.
- Cell Reports, Vol. 9, Issue 1
Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex
journal, November 2014
- Parmigiani, Anita; Nourbakhsh, Aida; Ding, Boxiao
- Cell Reports, Vol. 9, Issue 4
Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007
- Krissinel, Evgeny; Henrick, Kim
- Journal of Molecular Biology, Vol. 372, Issue 3
The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1
journal, November 2013
- Tsun, Zhi-Yang; Bar-Peled, Liron; Chantranupong, Lynne
- Molecular Cell, Vol. 52, Issue 4
mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery
journal, July 2002
- Kim, Do-Hyung; Sarbassov, Dos D.; Ali, Siraj M.
- Cell, Vol. 110, Issue 2
Surprising similarities in structure comparison
journal, June 1996
- Gibrat, Jean-Francois; Madej, Thomas; Bryant, Stephen H.
- Current Opinion in Structural Biology, Vol. 6, Issue 3
Regulation of TOR by small GTPases
journal, January 2012
- Durán, Raúl V.; Hall, Michael N.
- EMBO reports, Vol. 13, Issue 2
Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
journal, August 2016
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Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
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Chronic rapamycin treatment on the nutrient utilization and metabolism of juvenile turbot (Psetta maxima)
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Nutrients and growth factors in mTORC1 activation
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A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
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The Mechanism of Mycobacterium tuberculosis Alkylhydroperoxidase AhpD as Defined by Mutagenesis, Crystallography, and Kinetics
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Sestrin 2 Is Not a Reductase for Cysteine Sulfinic Acid of Peroxiredoxins
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Jalview Version 2--a multiple sequence alignment editor and analysis workbench
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Novel Role of the Small GTPase Rheb: Its Implication in Endocytic Pathway Independent of the Activation of Mammalian Target of Rapamycin
journal, March 2005
- Saito, K.
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Protein, amino acids and the control of food intake
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- Budanov, A. V.
- Science, Vol. 304, Issue 5670
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
journal, June 2008
- Sancak, Y.; Peterson, T. R.; Shaul, Y. D.
- Science, Vol. 320, Issue 5882
Structural Evidence for Common Ancestry of the Nuclear Pore Complex and Vesicle Coats
journal, November 2008
- Brohawn, S. G.; Leksa, N. C.; Spear, E. D.
- Science, Vol. 322, Issue 5906
mTORC1 Senses Lysosomal Amino Acids Through an Inside-Out Mechanism That Requires the Vacuolar H+-ATPase
journal, November 2011
- Zoncu, R.; Bar-Peled, L.; Efeyan, A.
- Science, Vol. 334, Issue 6056
A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1
journal, May 2013
- Bar-Peled, L.; Chantranupong, L.; Cherniack, A. D.
- Science, Vol. 340, Issue 6136
Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1
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- Wang, S.; Tsun, Z. -Y.; Wolfson, R. L.
- Science, Vol. 347, Issue 6218
Sestrin2 is a leucine sensor for the mTORC1 pathway
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- Wolfson, R. L.; Chantranupong, L.; Saxton, R. A.
- Science, Vol. 351, Issue 6268
mTOR as a central regulator of lifespan and aging
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Nutrient sensing and TOR signaling in yeast and mammals
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mTOR Complex 1 Implicated in Aphid/ Buchnera Host/Symbiont Integration
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X-Ray Diffraction data from Human Sestrin2, Leucine-bound, source of 5DJ4 structure
dataset, November 2017
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dataset, November 2017
- Saxton, Robert A.; Schwartz, Thomas U.
- SBGrid Data Bank
X-Ray Diffraction data from Human Sestrin2, pseudo-apo form, source of 5T0N structure
dataset, November 2017
- Saxton, Robert A.; Schwartz, Thomas U.
- SBGrid Data Bank
Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines
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Collaboration gets the most out of software
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Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
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Chronic rapamycin treatment on the nutrient utilization and metabolism of juvenile turbot (Psetta maxima)
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Nutrient sensing and TOR signaling in yeast and mammals
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mTOR Complex 1 Implicated in Aphid/ Buchnera Host/Symbiont Integration
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