title: Aβ40(L17A/F19A) mutant diminishes the aggregation and neurotoxicity of Aβ40.
abstract: Aggregated β-amyloid peptides (Aβ) are neurotoxic and responsible for neuronal death both in vitro and in vivo. From the structural point of view, Aβ self-aggregation involves a conformational change in the peptide. Here, we investigated the relationship between conformational changes and amino acid residues of Aβ(40). Urea unfolding in combination with NMR spectroscopy was applied to probe the stabilization of Aβ(40) conformation. L17 and F19 residues were found more sensitive to environmental changes than the other residues. Replacement of these two residues with alanine could stabilize the conformation of Aβ(40). Further analysis indicated that the Aβ(40)(L17A/F19A) mutant could diminish the aggregation and reduce the neurotoxicity. These results suggest that L17 and F19 are the critical residues responsible for conformational changes which may trigger neurotoxic cascade of Aβ(40).
authors.affiliation: Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Chen
authors.forename: Hsien-bin
authors.initials: HB
authors.lastname: Huang
authors.forename: Chi-Jen
authors.initials: CJ
authors.lastname: Lo
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Wang
authors.forename: Chia-Li
authors.initials: CL
authors.lastname: Su
authors.forename: Hsin-Tzu
authors.initials: HT
authors.lastname: Liu
authors.forename: Ming-Shi
authors.initials: MS
authors.lastname: Shiao
authors.forename: Ta-Hsien
authors.initials: TH
authors.lastname: Lin
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000235:genetics; D000544:Alzheimer Disease / Q000378:metabolism*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival; D006801:Humans; D007930:Leucine / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000187:drug effects*; D019906:Nuclear Magnetic Resonance, Biomolecular; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D051381:Rats; D014508:Urea / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D010649:Phenylalanine; D014508:Urea; D007930:Leucine; D000409:Alanine