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]
- Weill Cornell Medicine, New York, NY (United States)
- 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:
Comparative Protein Structure Modeling Using MODELLER
journal, November 2007
- Eswar, Narayanan; Webb, Ben; Marti-Renom, Marc A.
- Current Protocols in Protein Science, Vol. 50, Issue 1
Scalable molecular dynamics with NAMD
journal, January 2005
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A rapid, sensitive, and specific method for the determination of protein in dilute solution
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- Analytical Biochemistry, Vol. 56, Issue 2
VMD: Visual molecular dynamics
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Computational approaches to detect allosteric pathways in transmembrane molecular machines
journal, July 2016
- Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V.
- Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 7
Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT
journal, September 2012
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Coupled Global and Local Changes Direct Substrate Translocation by Neurotransmitter-Sodium Symporter Ortholog LeuT
journal, August 2013
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- Biophysical Journal, Vol. 105, Issue 3
Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter
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The bright future of single-molecule fluorescence imaging
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- Current Opinion in Chemical Biology, Vol. 20
The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site
journal, June 2008
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Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics
journal, December 2019
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A Simple Method for Automated Equilibration Detection in Molecular Simulations
journal, March 2016
- Chodera, John D.
- Journal of Chemical Theory and Computation, Vol. 12, Issue 4
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
The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems
journal, November 2016
- Cuendet, Michel A.; Weinstein, Harel; LeVine, Michael V.
- Journal of Chemical Theory and Computation, Vol. 12, Issue 12
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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- ACS Chemical Neuroscience, Vol. 6, Issue 11
Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2
journal, November 2017
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The Role of Local Hydration and Hydrogen-Bonding Dynamics in Ion and Solute Release from Ion-Coupled Secondary Transporters
journal, March 2011
- Zhao, Chunfeng; Noskov, Sergei Yu.
- Biochemistry, Vol. 50, Issue 11
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles
journal, August 2012
- Best, Robert B.; Zhu, Xiao; Shim, Jihyun
- Journal of Chemical Theory and Computation, Vol. 8, Issue 9
Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields
journal, November 1994
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High-Affinity Adaptors for Switchable Recognition of Histidine-Tagged Proteins
journal, July 2005
- Lata, Suman; Reichel, Annett; Brock, Roland
- Journal of the American Chemical Society, Vol. 127, Issue 29
Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
journal, June 2010
- Klauda, Jeffery B.; Venable, Richard M.; Freites, J. Alfredo
- The Journal of Physical Chemistry B, Vol. 114, Issue 23
Simple Allosteric Model for Membrane Pumps
journal, August 1966
- Jardetzky, Oleg
- Nature, Vol. 211, Issue 5052
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
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
Mechanism of chloride interaction with neurotransmitter:sodium symporters
journal, August 2007
- Zomot, Elia; Bendahan, Annie; Quick, Matthias
- Nature, Vol. 449, Issue 7163
Unlocking the molecular secrets of sodium-coupled transporters
journal, May 2009
- Krishnamurthy, Harini; Piscitelli, Chayne L.; Gouaux, Eric
- Nature, Vol. 459, Issue 7245
Single-molecule dynamics of gating in a neurotransmitter transporter homologue
journal, May 2010
- Zhao, Yongfang; Terry, Daniel; Shi, Lei
- Nature, Vol. 465, Issue 7295
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
X-ray structures of LeuT in substrate-free outward-open and apo inward-open states
journal, January 2012
- Krishnamurthy, Harini; Gouaux, Eric
- Nature, Vol. 481, Issue 7382
X-ray structure of dopamine transporter elucidates antidepressant mechanism
journal, September 2013
- Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric
- Nature, Vol. 503, Issue 7474
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
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