Interplay of histidine residues of the Alzheimer’s disease Aβ peptide governs its Zn-induced oligomerization

Abstract

Conformational changes of Aβ peptide result in its transformation from native monomeric state to the toxic soluble dimers, oligomers and insoluble aggregates that are hallmarks of Alzheimer’s disease (AD). Interactions of zinc ions with Aβ are mediated by the N-terminal Aβ1–16 domain and appear to play a key role in AD progression. There is a range of results indicating that these interactions trigger the Aβ plaque formation. We have determined structure and functional characteristics of the metal binding domains derived from several Aβ variants and found that their zinc-induced oligomerization is governed by conformational changes in the minimal zinc binding site 6HDSGYEVHH14. The residue H6 and segment 11EVHH14, which are part of this site are crucial for formation of the two zinc-mediated interaction interfaces in Aβ. These structural determinants can be considered as promising targets for rational design of the AD-modifying drugs aimed at blocking pathological Aβ aggregation.

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

“…A zinc‐bridged dimer was suggested recently to be a key intermediate in Aβ oligomerisation 39. If the former were true, the rate determined here would be an effective indicator.…”

“…[38] Az inc-bridged dimer was suggested recently to be ak ey intermediate in Ab oligomerisation. [39] If the former were true, the rate determined here would be an effective indicator.W en ote that under pseudofirst-order reactionc onditions (with nanomolarA b·Cu 2 + ,n ear physiological pH), the copper-bridged heterodimer was not well populated, as fluorescenceq uenching was almost fully recovered. Nevertheless, this condition might be representative of that in the synaptic clefts of neurons.…”

β‐Amyloid aggregation and heterogeneous nucleation

“…Research of the past two decades has led to a much improved understanding of the mechanisms of metal ion binding by Aβ peptides . There is a fundamental difference between the mechanism of metal ion binding by Aβ and that of the well‐structured metalloproteins .…”

A Binuclear Zinc Interaction Fold Discovered in the Homodimer of Alzheimer's Amyloid‐β Fragment with Taiwanese Mutation D7H

“…The metal‐binding domain Aβ(1–16) of the peptide with Taiwanese mutation exhibits extremely high propensity to aggregate in the presence of zinc ions (Supporting Information, Figure S1). Based on the molecular mechanism of formation of zinc‐bonded dimers of different Aβ isoforms, we hypothesized that zinc‐dependent aggregation of the metal‐binding domain of Aβ with Taiwanese mutation is determined by the properties of the fragment 1–10 (D7H‐Aβ(1–10)), where the relevant amino acid substitution is located. In this study, using NMR spectroscopy, mass spectrometry, EXAFS spectroscopy, and isothermal titration calorimetry (ITC), we have examined the behavior of this peptide in the presence of zinc ions.…”