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Dopamine transporter oligomerization involves the scaffold domain, but spares the bundle domain

Jayaraman, K., Morley, A. N., Szollosi, D., Wassenaar, T. A., Sitte, H. H. & Stockner, T., Jun-2018, In : PLoS Computational Biology. 14, 6, 25 p., 1006229.

Research output: Contribution to journalArticleAcademicpeer-review

  • Kumaresan Jayaraman
  • Alex N. Morley
  • Daniel Szollosi
  • Tsjerk A. Wassenaar
  • Harald H. Sitte
  • Thomas Stockner

The human dopamine transporter (hDAT) is located on presynaptic neurons, where it plays an essential role in limiting dopaminergic signaling by temporarily curtailing high neurotransmitter concentration through rapid re-uptake. Transport by hDAT is energized by transmembrane ionic gradients. Dysfunction of this transporter leads to disease states, such as Parkinson's disease, bipolar disorder or depression. It has been shown that hDAT and other members of the monoamine transporter family exist in oligomeric forms at the plasma membrane. Several residues are known to be involved in oligomerization, but interaction interfaces, oligomer orientation and the quarternary arrangement in the plasma membrane remain poorly understood. Here we examine oligomeric forms of hDAT using a direct approach, by following dimerization of two randomly-oriented hDAT transporters in 512 independent simulations, each being 2 mu s in length. We employed the DAFT (docking assay for transmembrane components) approach, which is an unbiased molecular dynamics simulation method to identify oligomers, their conformations and populations. The overall ensemble of a total of > 1 ms simulation time revealed a limited number of symmetric and asymmetric dimers. The identified dimer interfaces include all residues known to be involved in dimerization. Importantly, we find that the surface of the bundle domain is largely excluded from engaging in dimeric interfaces. Such an interaction would typically lead to inhibition by stabilization of one conformation, while substrate transport relies on a large scale rotation between the inward-facing and the outward-facing state.

Original languageEnglish
Article number1006229
Number of pages25
JournalPLoS Computational Biology
Volume14
Issue number6
Publication statusPublished - Jun-2018

    Keywords

  • HUMAN SEROTONIN TRANSPORTER, AMINOBUTYRIC-ACID TRANSPORTER-1, RAT GABA TRANSPORTER-1, PLASMA-MEMBRANE, MOLECULAR-DYNAMICS, NEUROTRANSMITTER TRANSPORTERS, TRANSMEMBRANE SEGMENT, CROSS-LINKING, FORCE-FIELD, PROTEIN

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