New structures help the modeling of toxic amyloidbeta ion channels

Trends Biochem Sci. 2008 Feb;33(2):91-100. doi: 10.1016/j.tibs.2007.10.007. Epub 2008 Jan 7.

Abstract

The mechanism of amyloid toxicity is poorly understood and there are two schools of thought in this hotly debated field: the first favors membrane destabilization by intermediate-to-large amyloid oligomers, with consequent thinning and non-specific ion leakage; the second favors ion-specific permeable channels lined by small amyloid oligomers. Published results currently support both mechanisms. However, the amyloidbeta (Abeta) peptide has recently been shown to form a U-shaped 'beta-strand-turn-beta-strand' structure. This structure and the available physiological data present a challenge for computational biology--to provide candidate models consistent with the experimental data. Modeling based on small Abeta oligomers containing extramembranous N-termini predicts channels with shapes and dimensions consistent with experimentally derived channel structures. These results support the hypothesis that small Abeta oligomers can form ion channels. Molecular dynamics modeling can provide blueprints of 3D structural conformations for many other amyloids whose membrane association is key to their toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Amyloid beta-Peptides* / chemistry
  • Amyloid beta-Peptides* / toxicity
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Ion Channels / chemistry*
  • Ion Channels / metabolism
  • Models, Molecular
  • Protein Conformation*
  • Protein Folding

Substances

  • Amyloid beta-Peptides
  • Ion Channels