Abstract
Serotonin transporter (SERT) modulates serotonergic signaling via re-uptake of serotonin in pre-synaptic cells. The inclusion in cholesterol-enriched membrane domains is crucial for SERT activity, suggesting a cross-talk between the protein and the sterol. Here, we develop a protocol to identify potential cholesterol interaction sites coupling statistical analysis to multi-microsecond coarse-grained molecular dynamics simulations of SERT in a previously validated raft-like membrane model. Six putative sites were found, including a putative CRAC motif on TM4 and a CARC motif on TM10. Among them, four hot-spots near regions related to ion binding, transport, and inhibition were detected. Our results encourage prospective studies to unravel mechanistic features of the transporter and related drug discovery implications.
Highlights
Serotonin transporter (SERT) is a membrane protein of the neurotransmitter sodium symporters (NSS) family
We present multi-microsecond coarse-grained molecular dynamics simulations (CG MD) of a state-of-the-art hSERT homology model in a raft-like membrane environment validated in our recent work [33]
The time threshold for the identification of outliers’ region was 1.31 μs, in very good agreement with the microsecond time-scale associated to specific protein-cholesterol interactions [47]. These results suggest a dual behavior on SERT-cholesterol interactions: while specific contacts are only marginally affected by the cholesterol enrichment, changes in membrane dynamic properties turned out to have a substantial effect on the duration of aspecific interactions
Summary
Serotonin transporter (SERT) is a membrane protein of the neurotransmitter sodium symporters (NSS) family. These secondary active transporters couple the diffusion of sodium, chloride and potassium ions down their electrochemical gradients to drive the re-uptake of substrates against their concentration. Several NSSs [2], including SERT [3], are associated to cholesterol-enriched membrane domains, called lipid rafts, which concur to transport modulation through changes in membrane properties or direct binding to specific sites on the protein surface [4,5,6,7]. Since transport rates are decreased in cholesterol depleted membranes in a dose dependent manner [8], it has been recently proposed that this sterol might regulate SERT functionality by inducing a transient conformation with high affinity for serotonin (outward-open state) [9].
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