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.
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