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

PLoS Comput Biol. 2018 Jan 12;14(1):e1005907. doi: 10.1371/journal.pcbi.1005907. eCollection 2018 Jan.

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 transmembrane helix 1a and 5 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 monoamine transporters (dopamine, serotonin and norepinephrine), suggesting that our findings might extend to the entire family.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Cholesterol / chemistry*
  • Computer Simulation
  • Crystallography, X-Ray
  • Dopamine / chemistry*
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Drosophila melanogaster
  • Humans
  • Lipid Bilayers
  • Molecular Dynamics Simulation
  • Neurotransmitter Agents / chemistry
  • Protein Conformation
  • Signal Transduction
  • Software
  • Synaptic Transmission
  • Vesicular Monoamine Transport Proteins / chemistry

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Lipid Bilayers
  • Neurotransmitter Agents
  • Vesicular Monoamine Transport Proteins
  • Cholesterol
  • Dopamine

Grants and funding

The research was funded by the Danish Council for Independent Research | Natural Sciences (DFF-4002-00502 and DFF-7014-00192B) and Medical Sciences (DFF – 4004-00309); URL: http://ufm.dk/en/research-and-innovation/councils-and-commissions/independent-research-fund-Denmark?set_language=en&cl=en. Grants from the Lundbeck Foundation (URL: https://www.lundbeckfonden.com/en/) and the Carlsberg Foundation (URL: http://www.carlsbergfondet.dk/en) are also acknowledged. Computations were made possible at the Grendel-cluster (http://www.cscaa.dk/grendel/hardware/) through the Centre for Scientific Computing Aarhus (URL: http://phys.au.dk/forskning/cscaa/) and Abacus 2.0 (URL: https://abacus.deic.dk/) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.