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Nat Commun. 2018 Jan 15;9(1):230. doi: 10.1038/s41467-017-02202-y.

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

Author information

1
Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
2
Department of Psychiatry, Division of Molecular Therapeutics, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032, USA.
3
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA.
4
Department of Psychiatry, Division of Molecular Therapeutics, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032, USA. jaj2@columbia.edu.
5
Department of Pharmacology, Columbia University College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY, 10032, USA. jaj2@columbia.edu.
6
Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. scb2005@med.cornell.edu.

Abstract

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.

PMID:
29335402
PMCID:
PMC5768729
DOI:
10.1038/s41467-017-02202-y
[Indexed for MEDLINE]
Free PMC Article

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