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Type: Journal article
Title: Effect of oxidation and mutation on the conformational dynamics and fibril assembly of amyloidogenic peptides derived from apolipoprotein C-II
Author: Scanlon, D.
Citation: Journal of Physical Chemistry B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, 2009; 113(42):14006-14014
Publisher: Amer Chemical Soc
Issue Date: 2009
ISSN: 1520-6106
Statement of
F. S. Legge, K. J. Binger, M. D. W. Griffin, G. J. Howlett, D. Scanlon, H. Treutlein, and I. Yarovsky
Abstract: The oxidation of methionine residues in proteins can inhibit the self-assembly of proteins to form amyloid fibrils. For human apolipoprotein (apo) C-II the oxidation of methionine at position 60 inhibits fibril formation by the mature protein and by the core peptides apoC-II(56-76) and apoC-II(60-70). To investigate the molecular nature of these effects, we carried out fully solvated, all-atom molecular dynamics simulations of the structural changes in apoC-II(56-76) associated with substitutions of oxidized methionine (Met ox) at position 60. The results with apoC-II(56-76) (Met ox) showed less flexibility in structure, leading to a perturbation of the hydrophobic core. Valine substitution at position 60 showed an increased tendency to explore a wide range of conformational space, whereas the behavior of the Gln substitution mutant was similar to the wild-type peptide. These simulations are consistent with kinetic measurements which showed that a Met60Gln substitution within apoC-II(56-76) had little effect on the rate of fibril formation whereas substitution of Met ox or Val at position 60 lead to significant inhibition of peptide fibril formation. The effects of amino acid modification and substitutions on the kinetics of peptide fibril formation differ from the effects observed with full-length apoC-II inferring that additional mechanisms are involved in fibril formation by mature apoC-II.
Keywords: Humans; Amyloid; Methionine; Peptides; Cluster Analysis; Amino Acid Substitution; Amino Acid Sequence; Protein Structure, Secondary; Oxidation-Reduction; Kinetics; Mutation; Molecular Sequence Data; Apolipoprotein C-II; Hydrophobic and Hydrophilic Interactions
Rights: © 2009 American Chemical Society
RMID: 0020106206
DOI: 10.1021/jp903842u
Grant ID:
Appears in Collections:Medical Sciences publications

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