Nineveh Yako
Copper binding and redox chemistry of the Aβ16 peptide and its variants: insights into determinants of copper-dependent reactivity
Yako, Nineveh; Young, Tessa R.; Cottam Jones, Jade M.; Hutton, Craig A.; Wedd, Anthony G.; Xiao, Zhiguang
Authors
Tessa R. Young
Jade M. Cottam Jones
Craig A. Hutton
Anthony G. Wedd
Zhiguang Xiao
Abstract
The metal-binding sites of Aβ peptides are dictated primarily by the coordination preferences of the metal ion. Consequently, Cu(I) is typically bound with two His ligands in a linear mode while Cu(II) forms a pseudo-square planar stereochemistry with the N-terminal amine nitrogen acting as an anchoring ligand. Several distinct combinations of other groups can act as co-ligands for Cu(II). A population of multiple binding modes is possible with the equilibrium position shifting sensitively with solution pH and the nature of the residues in the N-terminal region. This work examined the Cu(II) chemistry of the Aβ16 peptide and several variants that targeted these binding modes. The results are consistent with: (i) at pH < 7.8, the square planar site in CuII–Aβ16 consists primarily of a bidentate ligand provided by the carboxylate sidechain of Asp1 and the N-terminal amine supported by the imidazole sidechains of two His residues (designated here as component IA); it is in equilibrium with a less stable component IB in which the carboxylate ligand is substituted by the Asp1-Ala2 carbonyl oxygen. (ii) Both IA and IB convert to a common component II (apparent transition pKa ∼7.8 for IA and ∼6.5 for IB, respectively) featuring a tridentate ligand consisting of the N-terminal amine, the Asp1-Ala2 amide and the Ala2-Pro3 carbonyl; this stereochemistry is stabilized by two five-membered chelate rings. (iii) Component IA is stabilized for variant Aβ16-D1H, components I (both IA and IB) are imposed on Aβ16-A2P while the less stable IB is enforced on Aβ16-D1A (which is converted to component II at pH ∼6.5); (iv) components IA and IB share two His ligands with Cu(I) and are more reactive in redox catalysis than component II that features a highly covalent and less reactive amide N− ligand. The redox activity of IA is further enhanced for peptides with a His1 N-terminus that may act as a ligand for either Cu(I) or Cu(II) with lower re-organization energy required for redox-shuttling. This study provided insights into the determinants that regulate the reactivity of Cu–Aβ complexes.
Citation
Yako, N., Young, T. R., Cottam Jones, J. M., Hutton, C. A., Wedd, A. G., & Xiao, Z. (2017). Copper binding and redox chemistry of the Aβ16 peptide and its variants: insights into determinants of copper-dependent reactivity. Metallomics, 9(3), 278-291. https://doi.org/10.1039/c6mt00299d
Journal Article Type | Article |
---|---|
Acceptance Date | Jan 24, 2017 |
Online Publication Date | Jan 24, 2017 |
Publication Date | Mar 22, 2017 |
Deposit Date | Apr 30, 2018 |
Publicly Available Date | May 21, 2018 |
Journal | Metallomics |
Print ISSN | 1756-5901 |
Electronic ISSN | 1756-591X |
Publisher | Oxford University Press |
Peer Reviewed | Peer Reviewed |
Volume | 9 |
Issue | 3 |
Pages | 278-291 |
DOI | https://doi.org/10.1039/c6mt00299d |
Public URL | https://durham-repository.worktribe.com/output/1327913 |
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http://creativecommons.org/licenses/by/4.0/
Copyright Statement
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
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