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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) (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}
}

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

Citation Metrics:
Cited by: 55 works
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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
    • 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

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    • 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


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    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


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