title: A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes.
abstract: Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as "CARC"). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide. The CARC-cholesterol interaction is of high affinity, lipid-specific, concentration-dependent, and sensitive to single-point mutations. The CARC motif is generally located in the outer membrane leaflet and its reverse sequence CRAC in the inner one. Their simultaneous presence within the same transmembrane domain obeys a "mirror code" controlling protein-cholesterol interactions in the outer and inner membrane leaflets. Deciphering this code enabled us to elaborate guidelines for the detection of cholesterol-binding motifs in any membrane protein. Several representative examples of neurotransmitter receptors and ABC transporters with the dual CARC/CRAC motifs are presented. The biological significance and potential clinical applications of the mirror code are discussed.
authors.affiliation: EA-4674, Interactions Moléculaires et Systèmes Membranaires, Aix-Marseille Université, Marseille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
authors.affiliation: EA-4674, Interactions Moléculaires et Systèmes Membranaires, Aix-Marseille Université, Marseille, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Di Scala
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Evans
authors.affiliation: Centre for Biological Sciences/Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Philip T F
authors.initials: PT
authors.lastname: Williamson
authors.affiliation: Laboratory of Molecular Neurobiology, Biomedical Research Institute (BIOMED) UCA-CONICET, Faculty of Medical Sciences, Catholic University of Argentina, Buenos Aires, Argentina.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Barrantes
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D020816:Amino Acid Motifs; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D011950:Receptors, Cholinergic; D002784:Cholesterol