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Effects of mutation on the amyloidogenic propensity of apolipoprotein C-II(60-70) peptide

Nevena Todorova1, Andrew Hung, Simon M Maaser

  • 1Health Innovations Research Institute, School of Applied Sciences, RMIT University, Melbourne, VIC, Australia.

Physical Chemistry Chemical Physics : PCCP
|October 13, 2010
PubMed

Insights

Mutations to the amyloidogenic apoC-II(60-70) peptide affect fibril formation kinetics. While all mutated peptides formed fibrils, oxidation or glutamine substitution significantly slowed the process compared to wild-type and valine substitutions.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biophysics

Background:

  • Amyloidogenic peptides, such as apolipoprotein C-II(60-70) (apoC-II(60-70)), are implicated in various diseases.
  • Understanding the structural basis of peptide fibrillation is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the impact of specific mutations on the structure, dynamics, and fibrillation kinetics of the apoC-II(60-70) peptide.
  • To compare the behavior of wild-type, mutated, and oxidized apoC-II(60-70) peptides in monomeric and oligomeric states.

Main Methods:

  • Experimental methods including Thioflavin T (ThT) fluorescence assays to monitor fibril formation kinetics.
  • Computational methods, specifically molecular dynamics (MD) simulations, to analyze peptide structure, dynamics, and oligomer stability.

Main Results:

  • All investigated apoC-II(60-70) peptides (wild-type, Met60Gln, Met60Val, oxi-Met) formed fibrils, but with distinct kinetics.
  • Oxidized Met60 (oxi-Met) and Met60Gln substitutions significantly increased lag phases, indicating slower fibrillation.
  • MD simulations revealed that mutations influenced monomer structural features and increased flexibility, correlating with altered fibrillation rates. Stable tetrameric oligomers were observed, with mutations having minimal impact on tetramer stability.

Conclusions:

  • Single-point mutations and oxidation of Met60 in apoC-II(60-70) modulate fibrillation kinetics through effects on structure and dynamics.
  • The critical nucleus size for apoC-II(60-70) fibrillation may be small, as stable tetrameric oligomers were observed.
  • Fibrillation mechanisms for shorter apoC-II peptides differ from longer fragments and full-length protein, suggesting complex regulatory pathways.

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