Author:
Zeppelin Talia,Pedersen Kasper B.,Berglund Nils A.,Periole Xavier,Schiøtt Birgit
Abstract
AbstractThe 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.
Funder
Natur og Univers, Det Frie Forskningsråd
Novo Nordisk Fonden
Publisher
Springer Science and Business Media LLC
Reference54 articles.
1. Kristensen, A. S. et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 63, 585–640 (2011).
2. Norregaard, L. & Gether, U. The monoamine neurotransmitter transporters: structure, conformational changes and molecular gating. Curr. Opin. Drug. Disc. Dev. 4, 591–601 (2001).
3. Pramod, A. B., Foster, J., Carvelli, L. & Henry, L. K. SLC6 transporters: Structure, function, regulation, disease association and therapeutics. ABCs membr. Transp. Health Dis. (SLC Ser.) 34, 197–219 (2013).
4. Torres, G. E., Gainetdinov, R. R. & Caron, M. G. Plasma membrane monoamine transporters: structure, regulation and function. Nat. Rev. Neurosci. 4, 13–25 (2003).
5. Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).
Cited by
8 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献