title: Zn(++) binding disrupts the Asp(23)-Lys(28) salt bridge without altering the hairpin-shaped cross-β Structure of Aβ(42) 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.
authors.affiliation: Department of Chemical Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India.
authors.forename: Venus Singh
authors.initials: VS
authors.lastname: Mithu
authors.forename: Bidyut
authors.initials: B
authors.lastname: Sarkar
authors.forename: Debanjan
authors.initials: D
authors.lastname: Bhowmik
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Chandrakesan
authors.forename: Sudipta
authors.initials: S
authors.lastname: Maiti
authors.forename: Perunthiruthy K
authors.initials: PK
authors.lastname: Madhu
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D015032:Zinc / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001224:Aspartic Acid; D015032:Zinc; D008239:Lysine