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

Abstract 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. Dysf...

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Autores principales:	Talia Zeppelin, Kasper B. Pedersen, Nils A. Berglund, Xavier Periole, Birgit Schiøtt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8672ebf9631d40e4bbb79de58c8abfae
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spelling	oai:doaj.org-article:8672ebf9631d40e4bbb79de58c8abfae2021-12-02T14:21:53ZEffect of palmitoylation on the dimer formation of the human dopamine transporter10.1038/s41598-021-83374-y2045-2322https://doaj.org/article/8672ebf9631d40e4bbb79de58c8abfae2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83374-yhttps://doaj.org/toc/2045-2322Abstract 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.Talia ZeppelinKasper B. PedersenNils A. BerglundXavier PerioleBirgit SchiøttNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Talia Zeppelin Kasper B. Pedersen Nils A. Berglund Xavier Periole Birgit Schiøtt Effect of palmitoylation on the dimer formation of the human dopamine transporter
description	Abstract 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.
format	article
author	Talia Zeppelin Kasper B. Pedersen Nils A. Berglund Xavier Periole Birgit Schiøtt
author_facet	Talia Zeppelin Kasper B. Pedersen Nils A. Berglund Xavier Periole Birgit Schiøtt
author_sort	Talia Zeppelin
title	Effect of palmitoylation on the dimer formation of the human dopamine transporter
title_short	Effect of palmitoylation on the dimer formation of the human dopamine transporter
title_full	Effect of palmitoylation on the dimer formation of the human dopamine transporter
title_fullStr	Effect of palmitoylation on the dimer formation of the human dopamine transporter
title_full_unstemmed	Effect of palmitoylation on the dimer formation of the human dopamine transporter
title_sort	effect of palmitoylation on the dimer formation of the human dopamine transporter
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8672ebf9631d40e4bbb79de58c8abfae
work_keys_str_mv	AT taliazeppelin effectofpalmitoylationonthedimerformationofthehumandopaminetransporter AT kasperbpedersen effectofpalmitoylationonthedimerformationofthehumandopaminetransporter AT nilsaberglund effectofpalmitoylationonthedimerformationofthehumandopaminetransporter AT xavierperiole effectofpalmitoylationonthedimerformationofthehumandopaminetransporter AT birgitschiøtt effectofpalmitoylationonthedimerformationofthehumandopaminetransporter
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Effect of palmitoylation on the dimer formation of the human dopamine transporter

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