title: Hybrid In Silico/In Vitro Approaches for the Identification of Functional Cholesterol-Binding Domains in Membrane Proteins.
abstract: In eukaryotic cells, cholesterol is an important regulator of a broad range of membrane proteins, including receptors, transporters, and ion channels. Understanding how cholesterol interacts with membrane proteins is a difficult task because structural data of these proteins complexed with cholesterol are scarce. Here, we describe a dual approach based on in silico studies of protein-cholesterol interactions, combined with physico-chemical measurements of protein insertion into cholesterol-containing monolayers. Our algorithm is validated through careful analysis of the effect of key mutations within and outside the predicted cholesterol-binding site. Our method is illustrated by a complete analysis of cholesterol-binding to Alzheimer's β-amyloid peptide, a protein that penetrates the plasma membrane of brain cells through a cholesterol-dependent process.
authors.affiliation: EA-4674, Interactions Moléculaires et Systèmes Membranaires, Aix-Marseille Université, 163 Avenue de Luminy, 13288, Marseille Cedex 9, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Di Scala
authors.affiliation: EA-4674, Interactions Moléculaires et Systèmes Membranaires, Aix-Marseille Université, 163 Avenue de Luminy, 13288, Marseille Cedex 9, France. jacques.fantini@univ-amu.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D000072417:Protein Domains; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D016229:Amyloid beta-Peptides; D002784:Cholesterol
keywords: Alzheimer’s β-amyloid peptide; Cholesterol-binding motif; Langmuir monolayer; Molecular docking; Molecular dynamics simulations; Transmembrane domain