TY - JOUR
T1 - Mapping cholesterol interaction sites on serotonin transporter through coarse-grained molecular dynamics
AU - Ferraro, Mariarosaria
AU - Masetti, Matteo
AU - Recanatini, Maurizio
AU - Cavalli, Andrea
AU - Bottegoni, Giovanni
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84999737926&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0166196
DO - 10.1371/journal.pone.0166196
M3 - Article
C2 - 27907003
AN - SCOPUS:84999737926
SN - 1932-6203
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e0166196
ER -