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Title: 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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1126/science.aad2087

Citation Metrics:
Cited by: 55 works
Citation information provided by
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Works referenced in this record:

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    Works referencing / citing this record:

    Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes
    journal, May 2000


    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
    • DOI: 10.1002/prot.24364

    Basic Local Alignment Search Tool
    journal, October 1990


    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
    • DOI: 10.1006/jmbi.2000.4042

    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
    • DOI: 10.1016/j.bbrc.2006.03.220

    Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
    journal, April 2010


    mTOR Signaling in Growth Control and Disease
    journal, April 2012


    Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
    journal, September 2012


    Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling
    journal, September 2014


    The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
    journal, October 2014


    Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex
    journal, November 2014


    Inference of Macromolecular Assemblies from Crystalline State
    journal, September 2007


    The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1
    journal, November 2013


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    journal, July 2002


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    journal, June 1996

    • Gibrat, Jean-Francois; Madej, Thomas; Bryant, Stephen H.
    • Current Opinion in Structural Biology, Vol. 6, Issue 3
    • DOI: 10.1016/s0959-440x(96)80058-3

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    Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
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    • Nature, Vol. 536, Issue 7615
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    journal, June 2013

    • Dibble, Christian C.; Manning, Brendan D.
    • Nature Cell Biology, Vol. 15, Issue 6
    • DOI: 10.1038/ncb2763

    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
    • DOI: 10.1038/nprot.2007.321

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    • Zoncu, Roberto; Efeyan, Alejo; Sabatini, David M.
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    • DOI: 10.1038/nrm3025

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    Exploiting Cysteine Residues of SLC Membrane Transporters as Targets for Drugs
    journal, June 2019

    • Scalise, Mariafrancesca; Console, Lara; Galluccio, Michele
    • SLAS DISCOVERY: Advancing the Science of Drug Discovery, Vol. 24, Issue 9
    • DOI: 10.1177/2472555219856601

    EGF-activated PI3K/Akt signalling coordinates leucine uptake by regulating LAT3 expression in prostate cancer
    journal, July 2019

    • Zhang, Blake K.; Moran, Anne M.; Bailey, Charles G.
    • Cell Communication and Signaling, Vol. 17, Issue 1
    • DOI: 10.1186/s12964-019-0400-0

    Dietary restriction of amino acids for Cancer therapy
    journal, March 2020


    mTOR signaling in stem and progenitor cells
    journal, January 2018

    • Meng, Delong; Frank, Anderson R.; Jewell, Jenna L.
    • Development, Vol. 145, Issue 1
    • DOI: 10.1242/dev.152595

    Dynamin inhibitors block activation of mTORC1 by amino acids independently of dynamin
    journal, November 2017

    • Persaud, Avinash; Cormerais, Yann; Pouyssegur, Jacques
    • Journal of Cell Science, Vol. 131, Issue 1
    • DOI: 10.1242/jcs.211755

    Nutrient regulation of mTORC1 at a glance
    journal, November 2019

    • Condon, Kendall J.; Sabatini, David M.
    • Journal of Cell Science, Vol. 132, Issue 21
    • DOI: 10.1242/jcs.222570

    The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1
    journal, November 2016


    tRNA production links nutrient conditions to the onset of sexual differentiation through the TORC 1 pathway
    journal, January 2018


    Actionable Metabolic Pathways in Heart Failure and Cancer—Lessons From Cancer Cell Metabolism
    journal, June 2018

    • Karlstaedt, Anja; Schiffer, Walter; Taegtmeyer, Heinrich
    • Frontiers in Cardiovascular Medicine, Vol. 5
    • DOI: 10.3389/fcvm.2018.00071

    Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses
    journal, January 2018


    Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions
    journal, June 2019

    • Martano, Giuseppe; Borroni, Elena Monica; Lopci, Egesta
    • Frontiers in Molecular Neuroscience, Vol. 12
    • DOI: 10.3389/fnmol.2019.00151

    Metabolic Reprogramming of Non-Hodgkin's B-Cell Lymphomas and Potential Therapeutic Strategies
    journal, December 2018


    The Architecture of the Rag GTPase Signaling Network
    journal, June 2017

    • Nicastro, Raffaele; Sardu, Alessandro; Panchaud, Nicolas
    • Biomolecules, Vol. 7, Issue 4
    • DOI: 10.3390/biom7030048

    mTOR: A Cellular Regulator Interface in Health and Disease
    journal, January 2019

    • Boutouja, Fahd; Stiehm, Christian M.; Platta, Harald W.
    • Cells, Vol. 8, Issue 1
    • DOI: 10.3390/cells8010018

    Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients
    journal, February 2019

    • Giannopoulou, Aikaterini; Konstantakou, Eumorphia; Velentzas, Athanassios
    • International Journal of Molecular Sciences, Vol. 20, Issue 4
    • DOI: 10.3390/ijms20040937

    Differential Stimulation of Post-Exercise Myofibrillar Protein Synthesis in Humans Following Isonitrogenous, Isocaloric Pre-Exercise Feeding
    journal, July 2019

    • Davies, Robert W.; Bass, Joseph J.; Carson, Brian P.
    • Nutrients, Vol. 11, Issue 7
    • DOI: 10.3390/nu11071657

    Targeting Glutamine Metabolism for Cancer Treatment
    journal, January 2018


    GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor
    journal, May 2019