Zn++ Binding Disrupts the Asp23-Lys28 Salt Bridge without Altering the Hairpin-Shaped Cross-β Structure of Aβ42 Amyloid Aggregates

Abstract

Observations like high Zn(2+) concentrations in senile plaques found in the brains of Alzheimer's patients and evidences emphasizing the role of Zn(2+) in amyloid-β (Aβ)-induced toxicity have triggered wide interest in understanding the nature of Zn(2+)-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 Zn(2+). Structural studies have revealed that Zn(2+) has a binding site in the N-terminal region of monomeric Aβ, but not much is precisely known about the nature of binding of Zn(2+) with aggregated forms of Aβ or its effect on the molecular structure of these aggregates. Here, we explore this aspect of the Zn(2+)-Aβ interaction using one- and two-dimensional (13)C and (15)N solid-state NMR. We find that Zn(2+) 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 Asp(23) and Lys(28) by driving these residues into nonsalt-bridge-forming conformations. However, the cross-β structure of Aβ(42) 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 Aβ(42) but is significant for determining its fibrillar morphology and toxicity.

Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

“…Moreover, a closer examination of the contacts between Glu 22 or Asp 23 and Lys 28 in terms of the distance between the anionic and cationic residues suggests that a salt bridge formed between Asp 23 and Lys 28 occurs most frequently in the system Zn 2+ -Aβ40_m2 ( Figure 5). On the other hand, the salt bridge formed between Glu 22 and Lys 28 is more frequent than it does between Asp 23 and Lys 28 in the system Zn 2+ -Aβ40_m1. Although Glu 22 and Asp 23 are neighboring residues, they seem to be competitors for the formation of salt bridge with Lys 28 .…”

“…On the other hand, the salt bridge formed between Glu 22 and Lys 28 is more frequent than it does between Asp 23 and Lys 28 in the system Zn 2+ -Aβ40_m1. Although Glu 22 and Asp 23 are neighboring residues, they seem to be competitors for the formation of salt bridge with Lys 28 . This phenomenon has also been observed for Zn 2+ -free Aβ40 previously.…”

“…23 In contrast, according to the solidstate NMR studies of Zn 2+ binding to Aβ42 fibrils carried out at room temperature and pH 7.4, major structural changes happened in the N-terminus and the loop region (residues 23−31). 28 In particular, the salt bridge formed between Asp 23 and Lys 28 was found broken 28 (see discussion below). With regard to this work, either helix or random coil structure was identified from our simulations, depending on whether Asp 1 or Glu 11 is the oxygen ligand of Zn…”

“…30 between Asp 23 and Lys 28 . 23 In contrast, according to the solidstate NMR studies of Zn 2+ binding to Aβ42 fibrils carried out at room temperature and pH 7.4, major structural changes happened in the N-terminus and the loop region (residues 23−31).…”

“…Results from molecular dynamics simulations reveal that the conformational ensembles of different Zn 2+ -Aβ40 complexes are nonoverlapping. The formation of turn structure and, especially, the salt bridge between Glu 22 /Asp 23 and Lys 28 is dependent on specific Zn 2+ binding mode. Agreement with available NMR observations of secondary and tertiary structures could be better achieved if the two simulation results are considered together.…”