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}
}
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DOI: 10.1126/science.aad2087
DOI: 10.1126/science.aad2087
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Works referenced in this record:
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Structural Evidence for Common Ancestry of the Nuclear Pore Complex and Vesicle Coats
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Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
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Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling
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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.
- Proteins: Structure, Function, and Bioinformatics, Vol. 81, Issue 11
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
- Saxton, Robert A.; Chantranupong, Lynne; Knockenhauer, Kevin E.
- Nature, Vol. 536, Issue 7615
Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
journal, June 2013
- Dibble, Christian C.; Manning, Brendan D.
- Nature Cell Biology, Vol. 15, Issue 6
The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
journal, September 2007
- Niesen, Frank H.; Berglund, Helena; Vedadi, Masoud
- Nature Protocols, Vol. 2, Issue 9
mTOR: from growth signal integration to cancer, diabetes and ageing
journal, December 2010
- Zoncu, Roberto; Efeyan, Alejo; Sabatini, David M.
- Nature Reviews Molecular Cell Biology, Vol. 12, Issue 1
Amino acid signalling upstream of mTOR
journal, January 2013
- Jewell, Jenna L.; Russell, Ryan C.; Guan, Kun-Liang
- Nature Reviews Molecular Cell Biology, Vol. 14, Issue 3
Chronic rapamycin treatment on the nutrient utilization and metabolism of juvenile turbot (Psetta maxima)
journal, June 2016
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- Scientific Reports, Vol. 6, Issue 1
Nutrients and growth factors in mTORC1 activation
journal, July 2013
- Efeyan, Alejo; Sabatini, David M.
- Biochemical Society Transactions, Vol. 41, Issue 4
A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
journal, August 1995
- Boussif, O.; Lezoualc'h, F.; Zanta, M. A.
- Proceedings of the National Academy of Sciences, Vol. 92, Issue 16
The Mechanism of Mycobacterium tuberculosis Alkylhydroperoxidase AhpD as Defined by Mutagenesis, Crystallography, and Kinetics
journal, May 2003
- Koshkin, Aleksey; Nunn, Christine M.; Djordjevic, Snezana
- Journal of Biological Chemistry, Vol. 278, Issue 32
Sestrin 2 Is Not a Reductase for Cysteine Sulfinic Acid of Peroxiredoxins
journal, April 2009
- Woo, Hyun Ae; Bae, Soo Han; Park, Sunjoo
- Antioxidants & Redox Signaling, Vol. 11, Issue 4
Jalview Version 2--a multiple sequence alignment editor and analysis workbench
journal, January 2009
- Waterhouse, A. M.; Procter, J. B.; Martin, D. M. A.
- Bioinformatics, Vol. 25, Issue 9
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.
- Journal of Biochemistry, Vol. 137, Issue 3
Protein, amino acids and the control of food intake
journal, January 2009
- Potier, Mylène; Darcel, Nicolas; Tomé, Daniel
- Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 12, Issue 1
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
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Overview of the CCP 4 suite and current developments
journal, March 2011
- Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD
journal, April 2004
- 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
journal, January 2015
- Wang, S.; Tsun, Z. -Y.; Wolfson, R. L.
- Science, Vol. 347, Issue 6218
Sestrin2 is a leucine sensor for the mTORC1 pathway
journal, October 2015
- Wolfson, R. L.; Chantranupong, L.; Saxton, R. A.
- Science, Vol. 351, Issue 6268
mTOR as a central regulator of lifespan and aging
journal, January 2019
- Papadopoli, David; Boulay, Karine; Kazak, Lawrence
- F1000Research, Vol. 8
Nutrient sensing and TOR signaling in yeast and mammals
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- González, Asier; Hall, Michael N.
- The EMBO Journal, Vol. 36, Issue 4
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
- Saxton, Robert A.; Schwartz, Thomas
- SBGrid Data Bank
X-Ray Diffraction data from Human Sestrin2, Leucine-bound, source of 5DJ4 structure
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
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- 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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Modulation of the secretory pathway by amino-acid starvation
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Perspective: Protein Requirements and Optimal Intakes in Aging: Are We Ready to Recommend More Than the Recommended Daily Allowance?
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Autophagy: The Last Defense against Cellular Nutritional Stress
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Sestrin-3 modulation is essential for therapeutic efficacy of cucurbitacin B in lung cancer cells
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90th Anniversary Commentary: The mTORC1 Complex—A Central Player in the Control and Regulation of Amino Acid Sufficiency
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Regulation of mTORC1 by Small GTPases in Response to Nutrients
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LAT1 (SLC7A5) and CD98hc (SLC3A2) complex dynamics revealed by single-particle cryo-EM
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Branched-chain amino acids differently modulate catabolic and anabolic states in mammals: a pharmacological point of view: Branched-chain amino acids in health and disease
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T-cell metabolism governing activation, proliferation and differentiation; a modular view
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Leucine‐induced promotion of post‐absorptive EAA utilization and hepatic gluconeogenesis contributes to protein synthesis in skeletal muscle of dairy calves
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Lysosome: The metabolic signaling hub
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SAMTOR is an S -adenosylmethionine sensor for the mTORC1 pathway
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Regulation of Amino Acid Transport in Saccharomyces cerevisiae
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Mechanisms of Insulin Action and Insulin Resistance
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Sestrins at the Interface of ROS Control and Autophagy Regulation in Health and Disease
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Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
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Exploiting Cysteine Residues of SLC Membrane Transporters as Targets for Drugs
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EGF-activated PI3K/Akt signalling coordinates leucine uptake by regulating LAT3 expression in prostate cancer
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Dietary restriction of amino acids for Cancer therapy
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Dynamin inhibitors block activation of mTORC1 by amino acids independently of dynamin
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Nutrient regulation of mTORC1 at a glance
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The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1
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tRNA production links nutrient conditions to the onset of sexual differentiation through the TORC 1 pathway
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Actionable Metabolic Pathways in Heart Failure and Cancer—Lessons From Cancer Cell Metabolism
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Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses
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Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions
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Metabolic Reprogramming of Non-Hodgkin's B-Cell Lymphomas and Potential Therapeutic Strategies
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The Architecture of the Rag GTPase Signaling Network
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Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients
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Differential Stimulation of Post-Exercise Myofibrillar Protein Synthesis in Humans Following Isonitrogenous, Isocaloric Pre-Exercise Feeding
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Targeting Glutamine Metabolism for Cancer Treatment
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