title: Biochemical identification of a linear cholesterol-binding domain within Alzheimer's β amyloid peptide.
abstract: Alzheimer's β-amyloid (Aβ) peptides can self-organize into amyloid pores that may induce acute neurotoxic effects in brain cells. Membrane cholesterol, which regulates Aβ production and oligomerization, plays a key role in this process. Although several data suggested that cholesterol could bind to Aβ peptides, the molecular mechanisms underlying cholesterol/Aβ interactions are mostly unknown. On the basis of docking studies, we identified the linear fragment 22-35 of Aβ as a potential cholesterol-binding domain. This domain consists of an atypical concatenation of polar/apolar amino acid residues that was not previously found in cholesterol-binding motifs. Using the Langmuir film balance technique, we showed that synthetic peptides Aβ17-40 and Aβ22-35, but not Aβ1-16, could efficiently penetrate into cholesterol monolayers. The interaction between Aβ22-35 and cholesterol was fully saturable and lipid-specific. Single-point mutations of Val-24 and Lys-28 in Aβ22-35 prevented cholesterol binding, whereas mutations at residues 29, 33, and 34 had little to no effect. These data were consistent with the in silico identification of Val-24 and Lys-28 as critical residues for cholesterol binding. We conclude that the linear fragment 22-35 of Aβ is a functional cholesterol-binding domain that could promote the insertion of β-amyloid peptides or amyloid pore formation in cholesterol-rich membrane domains.
authors.affiliation: Laboratoire PPSN, EA 4674, Interactions Moléculaires et Systèmes Membranaires, Faculté des Sciences de St-Jérôme, Aix-Marseille Université, Service 331, 13331 Marseille cedex 20, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Di Scala
authors.forename: Nouara
authors.initials: N
authors.lastname: Yahi
authors.forename: Clément
authors.initials: C
authors.lastname: Lelièvre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Garmy
authors.forename: Henri
authors.initials: H
authors.lastname: Chahinian
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D001669:Biochemical Phenomena; D002784:Cholesterol / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D002784:Cholesterol