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

Bruno Alies (1) , Amandine Conte-Daban (1) , Stephanie Sayen (2) , Fabrice Collin (3, 1) , Isabelle Kieffer (4, 5) , Emmanuel Guillon (2) , Peter Faller (1) , Christelle Hureau (1)

1 LCC - Laboratoire de chimie de coordination
2 ICMR - Institut de Chimie Moléculaire de Reims - UMR 7312
3 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
4 OSUG - Observatoire des Sciences de l'Univers de Grenoble
5 ESRF - European Synchrotron Radiation Facility

The Zn(II) ion has been linked to Alzheimers disease (AD) due to its ability to modulate the aggregating properties of the amyloid-beta (A beta) peptide, where A beta aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to A beta is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the A beta 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(A beta) X-ray absorption spectroscopy fingerprint and on the Zn(II)-induced modifications of the A beta 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

Mots clés: Amyloid beta-Peptides / chemistry; Binding Sites; Histidine / chemistry Hydrogen-Ion Concentration; Proton Magnetic Resonance Spectroscopy; X-Ray Absorption Spectroscopy; Zinc / chemistry

Domaines: Chimie; Chimie de coordination

Bruno Alies, Amandine Conte-Daban, Stephanie Sayen, Fabrice Collin, Isabelle Kieffer, et al.. Zinc(II) Binding Site to the Amyloid-beta Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides. Inorganic Chemistry, 2016, 55 (20), pp.10499-10509. ⟨10.1021/acs.inorgchem.6b01733⟩. ⟨hal-01572932⟩