title: Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics.
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.
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Ferraro
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum - Università di Bologna, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum - Università di Bologna, Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum - Università di Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, Genova, Italy.|BiKi Technologies s.r.l., Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D012701:Serotonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008055:Lipids; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D002784:Cholesterol