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Effect of palmitoylation on the dimer formation of the human dopamine transporter

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The human dopamine transporter (hDAT) is one in three members of the monoamine transporter family (MAT). hDAT is essential for regulating the dopamine concentration in the synaptic cleft through dopamine reuptake into the presynaptic neuron; thereby controlling hDAT dopamine signaling. Dysfunction of the transporter is linked to several psychiatric disorders. hDAT and the other MATs have been shown to form oligomers in the plasma membrane, but only limited data exists on which dimeric and higher order oligomeric states are accessible and energetically favorable. In this work, we present several probable dimer conformations using computational coarse-grained self-assembly simulations and assess the relative stability of the different dimer conformations using umbrella sampling replica exchange molecular dynamics. Overall, the dimer conformations primarily involve TM9 and/or TM11 and/or TM12 at the interface. Furthermore, we show that a palmitoyl group (palm) attached to hDAT on TM12 modifies the free energy of separation for interfaces involving TM12, suggesting that S-palmitoylation may change the relative abundance of dimers involving TM12 in a biological context. Finally, a comparison of the identified interfaces of hDAT and palmitoylated hDAT to the human serotonin transporter interfaces and the leucine transporter interface, suggests similar dimer conformations across these protein family.

TidsskriftScientific Reports
StatusUdgivet - feb. 2021

Bibliografisk note

Funding Information:
The authors would like to acknowledge Jose C. Flores-Canales for having proofread the manuscript. Moreover, the research was made possible by the funding from the Danish Council for Independent Research Natural Sciences (DFF-4002-00502 and DFF-7014-00192B) and Medical Sciences (DFF – 4004-00309), the Lundbeck Foundation, and the Carlsberg Foundation. Computational resources were provided from the Novo Nordisk Foundation (NF18OC0032608) through allocations of time at the Centre for Scientific Computing Aarhus and Abacus 2.0.

Publisher Copyright:
© 2021, The Author(s).

Copyright 2021 Elsevier B.V., All rights reserved.

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