Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides

Abstract

The Zn(II) ion has been linked to Alzheimer’s disease (AD) due to its ability to modulate the aggregating properties of the amyloid-β (Aβ) peptide, where Aβ aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to Aβ is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the Aβ peptide, (ii) the multiplicity of anchoring sites, and (iii) the silent nature of the Zn(II) ion in most classical spectroscopies, this is a difficult task. To overcome these difficulties, we have investigated the impact of peptide alterations (mutations, N-terminal acetylation) on the Zn(Aβ) X-ray absorption spectroscopy fingerprint and on the Zn(II)-induced modifications of the Aβ peptides’ NMR signatures. We propose a tetrahedrally bound Zn(II) ion, in which the coordination sphere is made by two His residues and two carboxylate side chains. Equilibria between equivalent ligands for one Zn(II) binding position have also been observed, the predominant site being made by the side chains of His6, His13 or His14, Glu11, and Asp1 or Glu3 or Asp7, with a slight preference for Asp1.

Johann-type laboratory-scale x-ray absorption spectrometer with versatile detection modes

“…Such standard measurements are an ideal use for our instrument which we demonstrated recently in cases of mesoporous MnCo 2 O 4 and LaMnO 3+δ electrocatalysts [36,37], where we used K edge absorption spectroscopy to determine the oxidation states of Mn and Co in the bulk of the prepared nanoparticles. X-ray absorption spectroscopy is also suitable for noninvasive biochemical studies such as investigating the binding and activity of metallic ions in proteins and peptides [44,45] or metabolism of toxic elements in plants and animals [46,47]. With our instrument we have investigated the bioaccumulation of selenium in Pseudomonas sp.…”

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

“…Binding of zinc ions to D7H‐Aβ(1–10) causes significant change in the chemical shifts of peptide signals (Supporting Information, Figures S4, S5). Figure illustrates the changes between chemical shifts of free and zinc‐bound states, which are an order of magnitude higher than the observed for other studied Aβ fragments ,…”

“…They have linewidth comparable to the linewidth of the signals of free peptide. This distinguishes the peptide D7H‐Aβ(1–10) from all other previously studied Aβ fragments and isoforms, which show substantial line broadening upon the interaction with metal ions . Thus, interaction of the wild‐type fragment Aβ(1–10) with zinc ions is accompanied by a significant broadening of NMR resonances (Supporting Information, Figure S3).…”

Corrigendum: Structural Insights Into TDP-43 and Effects of Post-translational Modifications

“…The treatment, however, did not cause formation of CTD fragments, ubiquitination or phosphorylation of TDP-43 (Caragounis et al, 2010). Although an indirect route was not ruled out, especially via the generation of ROS through NMDA-or mitochondrial-mediated pathways by Zn 2+ , zinc ions are also known to bind and promote in vitro aggregation of Tau (Huang et al, 2014), alpha-synuclein (αSyn) (Valiente-Gabioud et al, 2012) and Amyloid-β Peptide(Aβ) (Alies et al, 2016). Altered zinc homeostasis is also suggested as a risk factor for several neurodegenerative disorders such as ALS or Alzheimer's disease [see review (Szewczyk, 2013)].…”