Membrane Binding Strongly Affecting the Dopamine Reactivity Induced by Copper Prion and Copper/Amyloid-β (Aβ) Peptides. A Ternary Copper/Aβ/Prion Peptide Complex Stabilized and Solubilized in Sodium Dodecyl Sulfate Micelles

Abstract

The combination between dyshomeostatic levels of catecholamine neurotransmitters and redox-active metals such as copper and iron exacerbates the oxidative stress condition that typically affects neurodegenerative diseases. We report a comparative study of the oxidative reactivity of copper complexes with amyloid-β (Aβ 40 ) and the prion peptide fragment 76-114 (PrP 76−114 ), containing the high-affinity binding site, toward dopamine and 4-methylcatechol, in aqueous buffer and in sodium dodecyl sulfate micelles, as a model membrane environment. The competitive oxidative and covalent modifications undergone by the peptides were also evaluated. The high binding affinity of Cu/peptide to micelles and lipid membranes leads to a strong reduction (Aβ 40 ) and quenching (PrP 76−114 ) of the oxidative efficiency of the binary complexes and to a stabilization and redox silencing of the ternary complex Cu II /Aβ 40 /PrP 76−114 , which is highly reactive in solution. The results improve our understanding of the pathological and protective effects associated with these complexes, depending on the physiological environment.

A Cu-bis(imidazole) Substrate Intermediate Is the Catalytically Competent Center for Catechol Oxidase Activity of Copper Amyloid-β

“…An initial experiment carried out to compare the oxidation of DA and 4-methylcatechol (MC) promoted by Cu II -NH 2 -Aβ 16 and Cu II -Ac-Aβ 16 (25–50 μM) at the saturating substrate concentration (3 mM) gave contradictory results (Figures and S1). As in our previous papers, ,, here, we follow the initial oxidation products of the catechols (dopaminochrome for DA and quinone for MC) that subsequently undergo further reactions up to the formation of a melanic type precipitate.…”

“…To this end, we investigated the reactivity of Cu II complexes with Aβ 16 , 12,13 S1). As in our previous papers, 20,25,26 here, we follow the initial oxidation products of the catechols (dopaminochrome for DA and quinone for MC) that subsequently undergo further reactions up to the formation of a melanic type precipitate.…”

Water‐Soluble Melanin–Protein–Fe/Cu Conjugates Derived from Norepinephrine as Reliable Models for Neuromelanin of Human Brain Locus Coeruleus

“…These data suggest the presence of essentially square planar copper(II) centers in the Cu-only conjugates and five-coordinated copper(II) centers in the Fe-Cu conjugates. [35] Overall, when inserted into the Peisach-Blumberg diagrams (Figure S7), the parameters suggest that copper(II) displays a mixed nitrogen/oxygen coordination, [36] as it is usually observed for Type 2 sites in copper proteins [37] and in copper(II) complexes with neuronal peptides like amyloid-β [38][39][40] and prions, [41,42] which all display CuN x O y coordination. This indicates that copper(II) is bound exclusively to the protein, βLG or fβLG, and not to the melanin component of the conjugates.…”

Interaction and Redox Chemistry between Iron, Dopamine, and Alpha-Synuclein C-Terminal Peptides

“…Last, the effect of Fe III -peptide complexes was evaluated by adding 20 µM of selected peptide before adding the metal ion. The whole protocol was repeated adding 20 mM of sodium dodecyl sulfate (SDS) to the buffer solution in order to mimic the effect of the membrane [ 27 ].…”