title: A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity.
abstract: A combination of hydrophobic and electrostatic interactions is important in initiating the aberrant self-assembly process that leads to formation of toxic oligomers and aggregates by multiple disease-related proteins, including amyloid β-protein (Aβ), whose self-assembly is believed to initiate brain pathogenesis in Alzheimer's disease. Lys residues play key roles in this process and participate in both types of interaction. They also are the target of our recently reported molecular tweezer inhibitors. To obtain further insight into the role of the two Lys residues in Aβ assembly and toxicity, here we substituted each by Ala in both Aβ40 and Aβ42 and studied the impact of the substitution on Aβ oligomerization, aggregation, and toxicity. Our data show that each substitution has a major impact on Aβ assembly and toxicity, with significant differences depending on peptide length (40 versus 42 amino acids) and the position of the substitution. In particular, Lys16→Ala substitution dramatically reduces Aβ toxicity. The data support the use of compounds targeting Lys residues specifically as inhibitors of Aβ toxicity and suggest that exploring the role of Lys residues in other disease-related amyloidogenic proteins may help understanding the mechanisms of aggregation and toxicity of these proteins.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Sinha
authors.forename: Dahabada H J
authors.initials: DH
authors.lastname: Lopes
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018360:Crystallography, X-Ray; D008239:Lysine / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D017510:Protein Folding; D055503:Protein Multimerization / Q000235:genetics; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D008239:Lysine