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Substrate-induced conformational dynamics of the dopamine transporter

Author

Listed:
  • Anne Kathrine Nielsen

    (University of Copenhagen
    University of Copenhagen)

  • Ingvar R. Möller

    (University of Copenhagen
    University of Copenhagen)

  • Yong Wang

    (University of Copenhagen)

  • Søren G. F. Rasmussen

    (University of Copenhagen)

  • Kresten Lindorff-Larsen

    (University of Copenhagen)

  • Kasper D. Rand

    (University of Copenhagen)

  • Claus J. Loland

    (University of Copenhagen)

Abstract

The dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-type Drosophila melanogaster dopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.

Suggested Citation

  • Anne Kathrine Nielsen & Ingvar R. Möller & Yong Wang & Søren G. F. Rasmussen & Kresten Lindorff-Larsen & Kasper D. Rand & Claus J. Loland, 2019. "Substrate-induced conformational dynamics of the dopamine transporter," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10449-w
    DOI: 10.1038/s41467-019-10449-w
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    Cited by:

    1. Solveig G. Schmidt & Mette Galsgaard Malle & Anne Kathrine Nielsen & Søren S.-R. Bohr & Ciara F. Pugh & Jeppe C. Nielsen & Ida H. Poulsen & Kasper D. Rand & Nikos S. Hatzakis & Claus J. Loland, 2022. "The dopamine transporter antiports potassium to increase the uptake of dopamine," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Jie Sun & Xiaoran Roger Liu & Shuang Li & Peng He & Weikai Li & Michael L. Gross, 2021. "Nanoparticles and photochemistry for native-like transmembrane protein footprinting," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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