PMID- 29329285
OWN - NLM
STAT- MEDLINE
DCOM- 20180618
LR  - 20231112
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 14
IP  - 1
DP  - 2018 Jan
TI  - A direct interaction of cholesterol with the dopamine transporter prevents its 
      out-to-inward transition.
PG  - e1005907
LID - 10.1371/journal.pcbi.1005907 [doi]
LID - e1005907
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 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.
FAU - Zeppelin, Talia
AU  - Zeppelin T
AD  - Department of Chemistry, Aarhus University, Aarhus C, Denmark.
FAU - Ladefoged, Lucy Kate
AU  - Ladefoged LK
AD  - Department of Chemistry, Aarhus University, Aarhus C, Denmark.
AD  - Interdisciplinary Nanoscience Center, Aarhus University, Aarhus C, Denmark.
FAU - Sinning, Steffen
AU  - Sinning S
AUID- ORCID: 0000-0001-6971-6929
AD  - Department of Chemistry, Aarhus University, Aarhus C, Denmark.
AD  - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus 
      University, Aarhus C, Denmark.
FAU - Periole, Xavier
AU  - Periole X
AD  - Department of Chemistry, Aarhus University, Aarhus C, Denmark.
FAU - Schiott, Birgit
AU  - Schiott B
AUID- ORCID: 0000-0001-9937-1562
AD  - Department of Chemistry, Aarhus University, Aarhus C, Denmark.
AD  - Interdisciplinary Nanoscience Center, Aarhus University, Aarhus C, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180112
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - 0 (Lipid Bilayers)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Amino Acid Motifs
MH  - Animals
MH  - Binding Sites
MH  - Cholesterol/*chemistry
MH  - Computer Simulation
MH  - Crystallography, X-Ray
MH  - Dopamine/*chemistry
MH  - Dopamine Plasma Membrane Transport Proteins/*metabolism
MH  - Drosophila melanogaster
MH  - Humans
MH  - Lipid Bilayers
MH  - Molecular Dynamics Simulation
MH  - Neurotransmitter Agents/chemistry
MH  - Protein Conformation
MH  - Signal Transduction
MH  - Software
MH  - Synaptic Transmission
MH  - Vesicular Monoamine Transport Proteins/chemistry
PMC - PMC5811071
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/01/13 06:00
MHDA- 2018/06/19 06:00
PMCR- 2018/01/12
CRDT- 2018/01/13 06:00
PHST- 2017/08/09 00:00 [received]
PHST- 2017/11/29 00:00 [accepted]
PHST- 2018/02/13 00:00 [revised]
PHST- 2018/01/13 06:00 [pubmed]
PHST- 2018/06/19 06:00 [medline]
PHST- 2018/01/13 06:00 [entrez]
PHST- 2018/01/12 00:00 [pmc-release]
AID - PCOMPBIOL-D-17-01204 [pii]
AID - 10.1371/journal.pcbi.1005907 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2018 Jan 12;14(1):e1005907. doi: 10.1371/journal.pcbi.1005907. 
      eCollection 2018 Jan.