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Title: The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor

Abstract

Neurotransmitter:sodium symporters (NSSs) in the SLC6 family terminate neurotransmission by coupling the thermodynamically favorable transport of ions to the thermodynamically unfavorable transport of neurotransmitter back into presynaptic neurons. Results from many structural, functional, and computational studies on LeuT, a bacterial NSS homolog, have provided critical insight into the mechanism of sodium-coupled transport, but the mechanism underlying substrate-specific transport rates is still not understood. We present a combination of molecular dynamics simulations, single-molecule fluorescence resonance energy transfer (smFRET) imaging, and measurements of Na + binding and substrate transport that reveals an allosteric substrate specificity mechanism. In this mechanism, residues F259 and I359 in the substrate binding pocket couple the binding of substrate to Na + release from the Na2 site by allosterically modulating the stability of a partially open, inward-facing state. We propose a model for transport selectivity in which residues F259 and I359 act as a volumetric sensor that inhibits the transport of bulky amino acids.

Authors:
 [1];  [1];  [1];  [1];  [2];  [2]; ORCiD logo [1]; ORCiD logo [1]
  1. Weill Cornell Medicine, New York, NY (United States)
  2. Columbia Univ., New York, NY (United States); New York State Psychiatric Inst. New York, NY (United States)
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC) (OLCF); Univ. of California, Oakland, CA (United States); UT-Battelle LLC/ORNL, Oak Ridge, TN (Unted States)
Sponsoring Org.:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR) (SC-21); National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1565765
Grant/Contract Number:  
[AC02-05CH11231; AC05-00OR22725; R21-MH099491; U54-GM087510; P01-DA012408; R01-DA041510; F31-DA035533; ACI-1053575; R01-GM116961]
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
[ Journal Volume: 116; Journal Issue: 32]; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., and Weinstein, Harel. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor. United States: N. p., 2019. Web. doi:10.1073/pnas.1903020116.
LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., & Weinstein, Harel. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor. United States. doi:10.1073/pnas.1903020116.
LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., and Weinstein, Harel. Fri . "The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor". United States. doi:10.1073/pnas.1903020116. https://www.osti.gov/servlets/purl/1565765.
@article{osti_1565765,
title = {The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor},
author = {LeVine, Michael V. and Terry, Daniel S. and Khelashvili, George and Siegel, Zarek S. and Quick, Matthias and Javitch, Jonathan A. and Blanchard, Scott C. and Weinstein, Harel},
abstractNote = {Neurotransmitter:sodium symporters (NSSs) in the SLC6 family terminate neurotransmission by coupling the thermodynamically favorable transport of ions to the thermodynamically unfavorable transport of neurotransmitter back into presynaptic neurons. Results from many structural, functional, and computational studies on LeuT, a bacterial NSS homolog, have provided critical insight into the mechanism of sodium-coupled transport, but the mechanism underlying substrate-specific transport rates is still not understood. We present a combination of molecular dynamics simulations, single-molecule fluorescence resonance energy transfer (smFRET) imaging, and measurements of Na+ binding and substrate transport that reveals an allosteric substrate specificity mechanism. In this mechanism, residues F259 and I359 in the substrate binding pocket couple the binding of substrate to Na+ release from the Na2 site by allosterically modulating the stability of a partially open, inward-facing state. We propose a model for transport selectivity in which residues F259 and I359 act as a volumetric sensor that inhibits the transport of bulky amino acids.},
doi = {10.1073/pnas.1903020116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = [32],
volume = [116],
place = {United States},
year = {2019},
month = {7}
}

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    Works referencing / citing this record:

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    • Eswar, Narayanan; Webb, Ben; Marti-Renom, Marc A.
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    • Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V.
    • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 7
    • DOI: 10.1016/j.bbamem.2016.01.010

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    journal, September 2012


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    journal, August 2013


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    journal, January 2018

    • LeVine, Michael V.; Cuendet, Michel A.; Razavi, Asghar M.
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    • DOI: 10.1016/j.bpj.2017.10.030

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    • Juette, Manuel F.; Terry, Daniel S.; Wasserman, Michael R.
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    • DOI: 10.1016/j.cbpa.2014.05.010

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    journal, December 2019


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    journal, April 2015


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    journal, February 2016


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    journal, March 2016


    CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field
    journal, December 2015

    • Lee, Jumin; Cheng, Xi; Swails, Jason M.
    • Journal of Chemical Theory and Computation, Vol. 12, Issue 1
    • DOI: 10.1021/acs.jctc.5b00935

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    • Journal of Chemical Theory and Computation, Vol. 12, Issue 12
    • DOI: 10.1021/acs.jctc.6b00841

    Spontaneous Inward Opening of the Dopamine Transporter Is Triggered by PIP 2 -Regulated Dynamics of the N-Terminus
    journal, August 2015


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    journal, November 2017


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    • Zhao, Chunfeng; Noskov, Sergei Yu.
    • Biochemistry, Vol. 50, Issue 11
    • DOI: 10.1021/bi101454f

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    • DOI: 10.1021/ct300400x

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    Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
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    • The Journal of Physical Chemistry B, Vol. 114, Issue 23
    • DOI: 10.1021/jp101759q

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    Residues crucial for maintaining short paths in network communication mediate signaling in proteins
    journal, January 2006

    • del Sol, Antonio; Fujihashi, Hirotomo; Amoros, Dolors
    • Molecular Systems Biology, Vol. 2, Issue 1
    • DOI: 10.1038/msb4100063

    Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters
    journal, July 2005

    • Yamashita, Atsuko; Singh, Satinder K.; Kawate, Toshimitsu
    • Nature, Vol. 437, Issue 7056
    • DOI: 10.1038/nature03978

    Mechanism of chloride interaction with neurotransmitter:sodium symporters
    journal, August 2007

    • Zomot, Elia; Bendahan, Annie; Quick, Matthias
    • Nature, Vol. 449, Issue 7163
    • DOI: 10.1038/nature06133

    Unlocking the molecular secrets of sodium-coupled transporters
    journal, May 2009

    • Krishnamurthy, Harini; Piscitelli, Chayne L.; Gouaux, Eric
    • Nature, Vol. 459, Issue 7245
    • DOI: 10.1038/nature08143

    Single-molecule dynamics of gating in a neurotransmitter transporter homologue
    journal, May 2010

    • Zhao, Yongfang; Terry, Daniel; Shi, Lei
    • Nature, Vol. 465, Issue 7295
    • DOI: 10.1038/nature09057

    Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue
    journal, April 2011

    • Zhao, Yongfang; Terry, Daniel S.; Shi, Lei
    • Nature, Vol. 474, Issue 7349
    • DOI: 10.1038/nature09971

    X-ray structures of LeuT in substrate-free outward-open and apo inward-open states
    journal, January 2012


    X-ray structure of dopamine transporter elucidates antidepressant mechanism
    journal, September 2013

    • Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric
    • Nature, Vol. 503, Issue 7474
    • DOI: 10.1038/nature12533

    Transport domain unlocking sets the uptake rate of an aspartate transporter
    journal, February 2015

    • Akyuz, Nurunisa; Georgieva, Elka R.; Zhou, Zhou
    • Nature, Vol. 518, Issue 7537
    • DOI: 10.1038/nature14158

    Neurotransmitter and psychostimulant recognition by the dopamine transporter
    journal, May 2015

    • Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric
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