Effects of mutation on the amyloidogenic propensity of apolipoprotein C-II60-70 peptide
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Date
2010-11-28
Source Title
Physical Chemistry, Chemical Physics - PCCP
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ROYAL SOC CHEMISTRY
Melbourne Authors
Affiliation
Biochemistry and Molecular Biology
Pharmacology and Therapeutics
Pharmacology and Therapeutics
Document Type
Journal Article
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Todorova, N., Hung, A., Maaser, S. M., Griffin, M. D. W., Karas, J., Howlett, G. J. & Yarovsky, I. (2010). Effects of mutation on the amyloidogenic propensity of apolipoprotein C-II60-70 peptide. Physical Chemistry Chemical Physics, 12 (44), pp.14762-14774. https://doi.org/10.1039/c0cp00299b.
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Abstract
Using experimental and computational methods we identified the effects of mutation on the structure and dynamics of the amyloidogenic peptide apoC-II(60-70), in monomeric and oligomeric states. Methionine (Met60) substitutions to hydrophilic Gln, hydrophobic Val, and methionine sulfoxide residues were investigated and the results compared with observations of fibril formation by the wild-type, Met60Gln, Met60Val, and oxidised Met60 (oxi-Met) apoC-II(60-70) peptides. ThT fluorescence measurements showed fibril formation by all peptides, however with different kinetics. The wild-type and Met60Val peptides formed fibrils fastest, while oxi-Met and Met60Gln peptides exhibited significantly longer lag phases. Molecular dynamics simulations showed that the mutated monomers exhibited structural features consistent with fibril-forming propensity, such as β-hairpin conformation and a hydrophobic core. However, important differences to the wild-type were also noted, such as increased structural flexibility (oxi-Met and Met60Gln systems) and a broader distribution of the aromatic angle orientation, which could contribute to the different fibrillation kinetics observed in these peptides. Our results also showed that the critical nucleus size for fibril formation by apoC-II(60-70) may not be very large, since tetrameric oligomers in anti-parallel configuration were very stable within the 100 ns of simulations. The single-point mutations Met60Val and Met60Gln had no significant effect on the structural stability of the tetramer. The rate of fibril formation by apoC-II(60-70) peptides was generally much faster compared to longer apoC-II(56-76) peptides. Also, the effects of amino acid modifications on the kinetics of peptide fibril formation differ from the effects observed for apoC-II(56-76) and full-length apoC-II, suggesting that additional mechanisms are involved in fibril formation by mature apoC-II.