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Single-molecule dynamics of gating in a neurotransmitter transporter homologue

Author

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  • Yongfang Zhao

    (Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, 630 W. 168th, New York, New York 10032, USA
    Columbia University College of Physicians and Surgeons, 630 W. 168th, New York, New York 10032, USA
    New York State Psychiatric Institute, New York, New York 10032, USA)

  • Daniel Terry

    (Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA)

  • Lei Shi

    (Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA
    HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA)

  • Harel Weinstein

    (Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA
    HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA)

  • Scott C. Blanchard

    (Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA)

  • Jonathan A. Javitch

    (Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, 630 W. 168th, New York, New York 10032, USA
    Columbia University College of Physicians and Surgeons, 630 W. 168th, New York, New York 10032, USA
    New York State Psychiatric Institute, New York, New York 10032, USA
    Columbia University College of Physicians and Surgeons, 630 W. 168th, New York, New York 10032, USA)

Abstract

Neurotransmitter:Na+ symporters (NSS) remove neurotransmitters from the synapse in a reuptake process that is driven by the Na+ gradient. Drugs that interfere with this reuptake mechanism, such as cocaine and antidepressants, profoundly influence behaviour and mood. To probe the nature of the conformational changes that are associated with substrate binding and transport, we have developed a single-molecule fluorescence imaging assay and combined it with functional and computational studies of the prokaryotic NSS homologue LeuT. Here we show molecular details of the modulation of intracellular gating of LeuT by substrates and inhibitors, as well as by mutations that alter binding, transport or both. Our direct observations of single-molecule transitions, reflecting structural dynamics of the intracellular region of the transporter that might be masked by ensemble averaging or suppressed under crystallographic conditions, are interpreted in the context of an allosteric mechanism that couples ion and substrate binding to transport.

Suggested Citation

  • Yongfang Zhao & Daniel Terry & Lei Shi & Harel Weinstein & Scott C. Blanchard & Jonathan A. Javitch, 2010. "Single-molecule dynamics of gating in a neurotransmitter transporter homologue," Nature, Nature, vol. 465(7295), pages 188-193, May.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7295:d:10.1038_nature09057
    DOI: 10.1038/nature09057
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    Cited by:

    1. Huanyu Z. Li & Ashley C. W. Pike & Irina Lotsaris & Gamma Chi & Jesper S. Hansen & Sarah C. Lee & Karin E. J. Rödström & Simon R. Bushell & David Speedman & Adam Evans & Dong Wang & Didi He & Leela Sh, 2024. "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Hyun Deok Song & Fangqiang Zhu, 2015. "Conformational Changes in Two Inter-Helical Loops of Mhp1 Membrane Transporter," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-19, July.
    3. Paul David Harris & Alessandra Narducci & Christian Gebhardt & Thorben Cordes & Shimon Weiss & Eitan Lerner, 2022. "Multi-parameter photon-by-photon hidden Markov modeling," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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