title: Amyloidogenic properties of a D/N mutated 12 amino acid fragment of the C-terminal domain of the Cholesteryl-Ester Transfer Protein (CETP).
abstract: The cholesteryl-ester transfer protein (CETP) facilitates the transfer of cholesterol esters and triglycerides between lipoproteins in plasma where the critical site for its function is situated in the C-terminal domain. Our group has previously shown that this domain presents conformational changes in a non-lipid environment when the mutation D(470)N is introduced. Using a series of peptides derived from this C-terminal domain, the present study shows that these changes favor the induction of a secondary β-structure as characterized by spectroscopic analysis and fluorescence techniques. From this type of secondary structure, the formation of peptide aggregates and fibrillar structures with amyloid characteristics induced cytotoxicity in microglial cells in culture. These supramolecular structures promote cell cytotoxicity through the formation of reactive oxygen species (ROS) and change the balance of a series of proteins that control the process of endocytosis, similar to that observed when β-amyloid fibrils are employed. Therefore, a fine balance between the highly dynamic secondary structure of the C-terminal domain of CETP, the net charge, and the physicochemical characteristics of the surrounding microenvironment define the type of secondary structure acquired. Changes in this balance might favor misfolding in this region, which would alter the lipid transfer capacity conducted by CETP, favoring its propensity to substitute its physiological function.
authors.affiliation: Institute of Cell Physiology, National Autonomus University of Mexico (UNAM), AP 70-243, 04510 Mexico, D.F., Mexico; E-Mail: vgarcia@emailifc.unam.mx.
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; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013696:Temperature
chemical_list: D016229:Amyloid beta-Peptides; D053480:Cholesterol Ester Transfer Proteins; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35)