title: Amyloid fibril formation of peptides derived from the C-terminus of CETP modulated by lipids.
abstract: Cholesteryl-ester transfer protein (CETP) is a plasmatic protein involved in neutral lipid transfer between lipoproteins. Focusing on the last 12 C-terminus residues we have previously shown that mutation D470N promotes a conformational change towards a β-secondary structure. In turn, this modification leads to the formation of oligomers and fibrillar structures, which cause cytotoxic effects similar to the ones provoked by amyloid peptides. In this study, we evaluated the role of specific lipid arrangements on the structure of peptide helix-Z (D470N) through the use of thioflavin T fluorescence, peptide bond absorbance, circular dichroism and electron microscopy. The results indicate that the use of micelles formed with lysophosphatidylcholine and lysophosphatidic acid (LPA) under neutral pH induce a conformational transition of peptide helix-Z containing a β-sheet conformation to a native α-helix structure, therefore avoiding the formation of amyloid fibrils. In contrast, incubation with phosphatidic acid does not change the profile for the β-sheet conformation. When the electrostatic charge at the surface of micelles or vesicles is regulated through the use of lipids such as phospholipid and LPA, minimal changes and the presence of β-structures were recorded. Mixtures with a positive net charge diminished the percentage of β-structure and the amount of amyloid fibrils. Our results suggest that the degree of solvation determined by the presence of a free hydroxyl group on lipids such as LPA is a key condition that can modulate the secondary structure and the consequent formation of amyloid fibrils in the highly flexible C-terminus domain of CETP.
authors.affiliation: Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México, DF, Mexico.
authors.forename: Victor
authors.initials: V
authors.lastname: García-González
authors.forename: Jaime
authors.initials: J
authors.lastname: Mas-Oliva
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry / Q000648:ultrastructure; D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000502:physiology*; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D053480:Cholesterol Ester Transfer Proteins; D008823:Micelles; D010446:Peptide Fragments