title: Copper binding and redox chemistry of the Aβ16 peptide and its variants: insights into determinants of copper-dependent reactivity.
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.
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Nineveh
authors.initials: N
authors.lastname: Yako
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Tessa R
authors.initials: TR
authors.lastname: Young
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Jade M
authors.initials: JM
authors.lastname: Cottam Jones
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hutton
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wedd
authors.affiliation: School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. z.xiao@florey.edu.au.
authors.forename: Zhiguang
authors.identifier: 0000-0001-6908-8897
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001205:Ascorbic Acid / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D003300:Copper; D001205:Ascorbic Acid; D010100:Oxygen