Substrate-induced conformational dynamics of the dopamine transporter

Anne Kathrine Nielsen, Ingvar R. Möller, Yong Wang, Søren G. F. Rasmussen, Kresten Lindorff-Larsen, Kasper D. Rand () and Claus J. Loland ()
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Anne Kathrine Nielsen: University of Copenhagen
Ingvar R. Möller: 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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10449-w

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