Zn⁺⁺ binding disrupts the Asp²³-Lys²⁸ salt bridge without altering the hairpin-shaped cross-β structure of Aβ₄₂ amyloid aggregates

Abstract

Observations like high Zn²⁺ concentrations in senile plaques found in the brains of Alzheimer's patients and evidences emphasizing the role of Zn²⁺ in amyloid-β (Aβ)-induced toxicity have triggered wide interest in understanding the nature of Zn²⁺-Aβ interaction. In vivo and in vitro studies have shown that aggregation kinetics, toxicity, and morphology of Aβ aggregates are perturbed in the presence of Zn²⁺. Structural studies have revealed that Zn²⁺ has a binding site in the N-terminal region of monomeric Aβ, but not much is precisely known about the nature of binding of Zn²⁺ with aggregated forms of Aβ or its effect on the molecular structure of these aggregates. Here, we explore this aspect of the Zn²⁺-Aβ interaction using one- and two-dimensional ¹³C and ¹⁵N solid-state NMR. We find that Zn²⁺ causes major structural changes in the N-terminal and the loop region connecting the two β-sheets. It breaks the salt bridge between the side chains of Asp²³ and Lys²⁸ by driving these residues into nonsalt-bridge-forming conformations. However, the cross-β structure of Aβ₄₂ aggregates remains unperturbed though the fibrillar morphology changes distinctly. We conclude that the salt bridge is not important for defining the characteristic molecular architecture of Aβ₄₂ but is significant for determining its fibrillar morphology and toxicity.