Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP2 -containing membranes

Proteins
George KhelashviliH Weinstein

Abstract

The dopamine transporter (DAT) is a transmembrane protein belonging to the family of neurotransmitter:sodium symporters (NSS). Members of the NSS are responsible for the clearance of neurotransmitters from the synaptic cleft, and for their translocation back into the presynaptic nerve terminal. The DAT contains long intracellular N- and C-terminal domains that are strongly implicated in the transporter function. The N-terminus (N-term), in particular, regulates the reverse transport (efflux) of the substrate through DAT. Currently, the molecular mechanisms of the efflux remain elusive in large part due to lack of structural information on the N-terminal segment. Here we report a computational model of the N-term of the human DAT (hDAT), obtained through an ab initio structure prediction, in combination with extensive atomistic molecular dynamics (MD) simulations in the context of a lipid membrane. Our analysis reveals that whereas the N-term is a highly dynamic domain, it contains secondary structure elements that remain stable in the long MD trajectories of interactions with the bilayer (totaling >2.2 μs). Combining MD simulations with continuum mean-field modeling we found that the N-term engages with lipid membranes through ...Continue Reading

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Citations

Nov 4, 2015·Frontiers in Pharmacology·Julie GrouleffBirgit Schiøtt
Mar 24, 2016·Biochimica Et Biophysica Acta·Sanja Pöyry, Ilpo Vattulainen
Apr 8, 2015·Biochimica Et Biophysica Acta·George Khelashvili, Harel Weinstein
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Jun 20, 2019·Open Biology·Emmanuel Mikros, George Diallinas
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Dec 21, 2019·Neurochemical Research·Jawad A KhanThomas Stockner
Jan 13, 2018·PLoS Computational Biology·Talia ZeppelinBirgit Schiøtt
Aug 9, 2020·Journal of Neurochemistry·Kumaresan JayaramanThomas Stockner
Sep 27, 2019·Frontiers in Molecular Biosciences·Deepthi JosephAravind Penmatsa
Jul 31, 2016·The Journal of Biological Chemistry·George KhelashviliHarel Weinstein
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Jun 12, 2020·Journal of Chemical Information and Modeling·Genoveva RojasAriela Vergara-Jaque
Feb 14, 2019·Chemical Reviews·Valentina CorradiD Peter Tieleman

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