The role of histidines in amyloid β fibril assembly

FEBS Lett. 2017 Apr;591(8):1167-1175. doi: 10.1002/1873-3468.12616. Epub 2017 Apr 3.

Abstract

Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH.

Keywords: abeta; amyloid; fibril; histidine; stability; surface plasmon resonance.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Amyloid / chemistry
  • Amyloid / metabolism*
  • Amyloid / ultrastructure
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Histidine / chemistry*
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Microscopy, Electron, Transmission
  • Mutation
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Protein Stability
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Surface Plasmon Resonance

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Recombinant Proteins
  • amyloid beta-protein (1-40)
  • Histidine