Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 32, Pages 15947-15956Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1903020116
Keywords
allostery; transporters; neurotransmitters
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Funding
- NIH [R21 MH099491, U54 GM087510, P01 DA012408, R01 DA041510, F31 DA035533, R01 GM116961]
- Office of Science of the US Department of Energy [DE-AC05-00OR22725, DE-AC02-05CH11231]
- National Science Foundation [ACI-1053575]
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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 1359 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 1359 act as a volumetric sensor that inhibits the transport of bulky amino acids.
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