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Title: A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport

Abstract

Here, neurotransmitter:sodium symporters (NSS), targets of antidepressants and psychostimulants, clear neurotransmitters from the synaptic cleft through sodium (Na+)-coupled transport. Substrate and Na+ are thought to be transported from the extracellular to intracellular space through an alternating access mechanism by coordinated conformational rearrangements in the symporter that alternately expose the binding sites to each side of the membrane. However, the mechanism by which the binding of ligands coordinates conformational changes occurring on opposite sides of the membrane is not well understood. Here, we report the use of single-molecule fluorescence resonance energy transfer (smFRET) techniques to image transitions between distinct conformational states on both the extracellular and intracellular sides of the prokaryotic NSS LeuT, including partially open intermediates associated with transport activity. The nature and functional context of these hitherto unidentified intermediate states shed new light on the allosteric mechanism that couples substrate and Na+ symport by the NSS family through conformational dynamics.

Authors:
ORCiD logo [1];  [2];  [2];  [3];  [3];  [1]; ORCiD logo [3];  [4];  [1]
+ Show Author Affiliations
  1. Weill Cornell Medicine, New York, NY (United States). Dept. of Physiology and Biophysics
  2. Columbia Univ. College of Physicians and Surgeons and New York State Psychiatric Inst, New York, NY (United States). Dept. of Psychiatry
  3. Weill Cornell Medicine, New York, NY (United States). Dept. of Physiology and Biophysics and HRH Prince Alwaleed Bin Talal Bin Abdulazaz Alsaud Inst. for Computational Biomedicine
  4. Columbia Univ. College of Physicians and Surgeons and New York State Psychiatric Inst, New York, NY (United States). Dept. of Psychiatry and Dept. of Pharmacology
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1489406
Grant/Contract Number:  
AC05-00OR22725; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Terry, Daniel S., Kolster, Rachel A., Quick, Matthias, LeVine, Michael V., Khelashvili, George, Zhou, Zhou, Weinstein, Harel, Javitch, Jonathan A., and Blanchard, Scott C. A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport. United States: N. p., 2018. Web. doi:10.1038/s41467-017-02202-y.
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Terry, Daniel S., Kolster, Rachel A., Quick, Matthias, LeVine, Michael V., Khelashvili, George, Zhou, Zhou, Weinstein, Harel, Javitch, Jonathan A., & Blanchard, Scott C. A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport. United States. https://doi.org/10.1038/s41467-017-02202-y
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Terry, Daniel S., Kolster, Rachel A., Quick, Matthias, LeVine, Michael V., Khelashvili, George, Zhou, Zhou, Weinstein, Harel, Javitch, Jonathan A., and Blanchard, Scott C. Mon . "A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport". United States. https://doi.org/10.1038/s41467-017-02202-y. https://www.osti.gov/servlets/purl/1489406.
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@article{osti_1489406,
title = {A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport},
author = {Terry, Daniel S. and Kolster, Rachel A. and Quick, Matthias and LeVine, Michael V. and Khelashvili, George and Zhou, Zhou and Weinstein, Harel and Javitch, Jonathan A. and Blanchard, Scott C.},
abstractNote = {Here, neurotransmitter:sodium symporters (NSS), targets of antidepressants and psychostimulants, clear neurotransmitters from the synaptic cleft through sodium (Na+)-coupled transport. Substrate and Na+ are thought to be transported from the extracellular to intracellular space through an alternating access mechanism by coordinated conformational rearrangements in the symporter that alternately expose the binding sites to each side of the membrane. However, the mechanism by which the binding of ligands coordinates conformational changes occurring on opposite sides of the membrane is not well understood. Here, we report the use of single-molecule fluorescence resonance energy transfer (smFRET) techniques to image transitions between distinct conformational states on both the extracellular and intracellular sides of the prokaryotic NSS LeuT, including partially open intermediates associated with transport activity. The nature and functional context of these hitherto unidentified intermediate states shed new light on the allosteric mechanism that couples substrate and Na+ symport by the NSS family through conformational dynamics.},
doi = {10.1038/s41467-017-02202-y},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {Mon Jan 15 00:00:00 EST 2018},
month = {Mon Jan 15 00:00:00 EST 2018}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1038/s41467-017-02202-y
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Cited by: 30 works
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Figures / Tables:

Fig. 1 Fig. 1 : Detection of intermediate-FRET states at extracellular and intracellular sides of LeuT. a Cartoon representation of LeuT showing the extracellularlabeling sites K239C and H480C as orange stars with TM11 and EL3 hidden for clarity. The arrow highlights the axis of motion expected in FRET experiments from relative positionsmore » of TM6a in crystal structures with closed (red, 3TT3), intermediate (yellow, 2A65), and open (green, 3TT1) extracellular sides. b Representative raw (blue) and filtered (cyan) smFRET trace from the extracellular side (K239C/H480C) in the absence of Na+ and substrate. c Histogram of the FRET values in b. d Histogram of all FRET values in all traces (gray bars), fitted with a Gaussian distribution for each FRET state (colored lines), along with the summed model distribution (black line). e–h As in a–d, but monitoring FRET from the intracellular perspective (H7C/ R86C) and the movements of the N terminus« less
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X-ray structure of dopamine transporter elucidates antidepressant mechanism
journal, September 2013

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Substrate-dependent proton antiport in neurotransmitter:sodium symporters
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journal, February 2016

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journal, September 2016

  • Billesbølle, Christian B.; Mortensen, Jonas S.; Sohail, Azmat
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journal, February 2016

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Plasma membrane monoamine transporters: structure, regulation and function
journal, January 2003

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  • Nature Reviews Neuroscience, Vol. 4, Issue 1
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Experimental conditions can obscure the second high-affinity site in LeuT
journal, January 2012

  • Quick, Matthias; Shi, Lei; Zehnpfennig, Britta
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journal, April 2014

  • Kazmier, Kelli; Sharma, Shruti; Quick, Matthias
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A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters
journal, October 2014

  • Malinauskaite, Lina; Quick, Matthias; Reinhard, Linda
  • Nature Structural & Molecular Biology, Vol. 21, Issue 11
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Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport
journal, April 2019

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter
journal, January 2017

  • Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel
  • Scientific Reports, Vol. 7, Issue 1
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Energy landscape of LeuT from molecular simulations
journal, December 2015

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Mechanism for alternating access in neurotransmitter transporters
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Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer
journal, February 2017

  • Adhikary, Suraj; Deredge, Daniel J.; Nagarajan, Anu
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 10
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Mechanism of the Association between Na + Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters
journal, April 2015

  • Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng
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Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter
journal, September 2015

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Two Na + Sites Control Conformational Change in a Neurotransmitter Transporter Homolog
journal, November 2015

  • Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu
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Common Folds and Transport Mechanisms of Secondary Active Transporters
journal, May 2013

Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle
journal, October 2014

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    • DOI: 10.3389/fmolb.2019.00096
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