Single-molecule dynamics of gating in a neurotransmitter transporter homologue

Yongfang Zhao, Daniel Terry, Lei Shi, Harel Weinstein, Scott C. Blanchard () and Jonathan A. Javitch ()
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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
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
Harel Weinstein: 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

Nature, 2010, vol. 465, issue 7295, 188-193

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09057

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