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

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          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 electrostatic interactions with the charged lipids PIP2 (phosphatidylinositol 4,5-Biphosphate) or PS (phosphatidylserine) that are present in these bilayers. We identify specific motifs along the N-term implicated in such interactions and show that differential modes of N-term/membrane association result in differential positioning of the structured segments on the membrane surface. These results will inform future structure-based studies that will elucidate the mechanistic role of the N-term in DAT function.

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          Author and article information

          Journal
          Proteins
          Proteins
          1097-0134
          0887-3585
          May 2015
          : 83
          : 5
          Affiliations
          [1 ] Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, 10065.
          Article
          NIHMS671635
          10.1002/prot.24792
          25739722
          216e928c-c185-4a52-9d12-5fb3290c0f8b
          © 2015 Wiley Periodicals, Inc.
          History

          amphetamine,efflux,electrostatics,molecular dynamics,neurotransmitter transporter,phosphorylation,signaling,sodium symporter

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