A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition

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A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition. / Zeppelin, Talia; Ladefoged, Lucy Kate; Sinning, Steffen; Periole, Xavier; Schiøtt, Birgit.

In: PLOS Computational Biology, Vol. 14, No. 1, e1005907, 01.01.2018.

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@article{e7957839ae16406bbee132867e010114,
title = "A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition",
abstract = "Monoamine transporters (MATs) carry out neurotransmitter reuptake from the synaptic cleft, a key step in neurotransmission, which is targeted in the treatment of neurological disorders. Cholesterol (CHOL), a major component of the synaptic plasma membrane, has been shown to exhibit a modulatory effect on MATs. Recent crystal structures of the dopamine transporter (DAT) revealed the presence of two conserved CHOL-like molecules, suggesting a functional protein-CHOL direct interaction. Here, we present extensive atomistic molecular dynamics (MD) simulations of DAT in an outward-facing conformation. In the absence of bound CHOL, DAT undergoes structural changes reflecting early events of dopamine transport: transition to an inward-facing conformation. In contrast, in the presence of bound CHOL, these conformational changes are inhibited, seemingly by an immobilization of the intracellular interface of TM1a and TM5 by CHOL. We also provide evidence, from coarse grain MD simulations that the CHOL sites observed in the DAT crystal structures are preserved in all human transporters (dopamine, serotonin and norepinephrine), suggesting that our findings might extend to the entire family.",
author = "Talia Zeppelin and Ladefoged, {Lucy Kate} and Steffen Sinning and Xavier Periole and Birgit Schi{\o}tt",
year = "2018",
month = jan,
day = "1",
doi = "10.1371/journal.pcbi.1005907",
language = "English",
volume = "14",
journal = "P L o S Computational Biology (Online)",
issn = "1553-7358",
publisher = "public library of science",
number = "1",

}

RIS

TY - JOUR

T1 - A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition

AU - Zeppelin, Talia

AU - Ladefoged, Lucy Kate

AU - Sinning, Steffen

AU - Periole, Xavier

AU - Schiøtt, Birgit

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Monoamine transporters (MATs) carry out neurotransmitter reuptake from the synaptic cleft, a key step in neurotransmission, which is targeted in the treatment of neurological disorders. Cholesterol (CHOL), a major component of the synaptic plasma membrane, has been shown to exhibit a modulatory effect on MATs. Recent crystal structures of the dopamine transporter (DAT) revealed the presence of two conserved CHOL-like molecules, suggesting a functional protein-CHOL direct interaction. Here, we present extensive atomistic molecular dynamics (MD) simulations of DAT in an outward-facing conformation. In the absence of bound CHOL, DAT undergoes structural changes reflecting early events of dopamine transport: transition to an inward-facing conformation. In contrast, in the presence of bound CHOL, these conformational changes are inhibited, seemingly by an immobilization of the intracellular interface of TM1a and TM5 by CHOL. We also provide evidence, from coarse grain MD simulations that the CHOL sites observed in the DAT crystal structures are preserved in all human transporters (dopamine, serotonin and norepinephrine), suggesting that our findings might extend to the entire family.

AB - Monoamine transporters (MATs) carry out neurotransmitter reuptake from the synaptic cleft, a key step in neurotransmission, which is targeted in the treatment of neurological disorders. Cholesterol (CHOL), a major component of the synaptic plasma membrane, has been shown to exhibit a modulatory effect on MATs. Recent crystal structures of the dopamine transporter (DAT) revealed the presence of two conserved CHOL-like molecules, suggesting a functional protein-CHOL direct interaction. Here, we present extensive atomistic molecular dynamics (MD) simulations of DAT in an outward-facing conformation. In the absence of bound CHOL, DAT undergoes structural changes reflecting early events of dopamine transport: transition to an inward-facing conformation. In contrast, in the presence of bound CHOL, these conformational changes are inhibited, seemingly by an immobilization of the intracellular interface of TM1a and TM5 by CHOL. We also provide evidence, from coarse grain MD simulations that the CHOL sites observed in the DAT crystal structures are preserved in all human transporters (dopamine, serotonin and norepinephrine), suggesting that our findings might extend to the entire family.

UR - http://www.scopus.com/inward/record.url?scp=85041402165&partnerID=8YFLogxK

U2 - 10.1371/journal.pcbi.1005907

DO - 10.1371/journal.pcbi.1005907

M3 - Journal article

C2 - 29329285

AN - SCOPUS:85041402165

VL - 14

JO - P L o S Computational Biology (Online)

JF - P L o S Computational Biology (Online)

SN - 1553-7358

IS - 1

M1 - e1005907

ER -