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

LeVine, Michael V.; Terry, Daniel S.; Khelashvili, George; Siegel, Zarek S.; Quick, Matthias; Javitch, Jonathan A.; Blanchard, Scott C.; Weinstein, Harel

doi:10.1073/pnas.1903020116

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

Journal Article · Fri Jul 19 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1903020116· OSTI ID:1565765

LeVine, Michael V. ^[1]; Terry, Daniel S. ^[1]; Khelashvili, George ^[1]; Siegel, Zarek S. ^[1]; Quick, Matthias ^[2]; Javitch, Jonathan A. ^[2]; ^[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)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC) (OLCF); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility; UT-Battelle LLC/ORNL, Oak Ridge, TN (Unted States); Univ. of California, Oakland, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR) (SC-21)

Grant/Contract Number:: AC02-05CH11231; AC05-00OR22725

OSTI ID:: 1565765

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 32 Vol. 116; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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