ИСТИНА

Zinc-induced oligomerization of amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer’s disease (AD). Interactions of zinc ions with Aβ are mediated by the N-terminal Aβ1-16 domain. Mutations and modifications in the metal binding domain Aβ1-16 crucially affect its zinc-induced oligomerization by changing intermolecular zinc mediated interface. Interaction of zinc ions with the metal binding domains derived from several Aβ variants were studied using the methods of NMR spectroscopy. NMR spectroscopy allows to identify the centers of chelation of the metal ions, stoichiometry of zinc-peptide interaction, to determine structure of the formed complexes, and dynamic processes accompanying their formation. A zinc-induced dimerization of the native Aβ1-16 isoform and the fragments carrying familial English (H6R) and Taiwanese (D7H) mutation was found. Zinc-induced peptide interaction is governed by conformational changes in the minimal zinc binding site 6HDSGYEVHH14. Novel binuclear zinc interaction fold in the dimer structure of the D7H-Aβ fragments has been discovered. We have determined high-resolution structure of the formed peptide dimers in solution. Novel zinc binding site in the peptide that contains the phosphorylated Ser8 (pS8) residue has been discovered. In an attempt to reveal the mechanism of rats’ resistance to Alzheimer’s disease, the structure of the metal binding domain of rat beta-amyloid in the presence of zinc ions has been determined. Zinc-induced oligomerization of the all the studied Aβ fragments has been shown to follow the same molecular mechanism: (i) peptide dimer is formed through the primary zinc-mediated interface 11EVHH14; (ii) residues H6, H13, H7, pS8 and E3 in various Аβ isoforms are realigned creating the second zinc-dependent interface in each subunit; (iii) the dimer becomes a seed of subsequent zinc-dependent oligomerization. Targeting of Aβ zinc-mediated interfaces may provide a therapeutic route for AD treatment.