Binding and Reactivity of Copper to R₁ and R₃ Fragments of tau Protein

Abstract

Tau protein is present in significant amounts in neurons, where it contributes to the stabilization of microtubules. Insoluble neurofibrillary tangles of tau are associated with several neurological disorders known as tauopathies, among which is Alzheimer’s disease. In neurons, tau binds tubulin through its microtubule binding domain which comprises four imperfect repeats (R1–R4). The histidine residues contained in these fragments are potential binding sites for metal ions and are located close to the regions that drive the formation of amyloid aggregates of tau. In this study, we present a detailed characterization through potentiometric and spectroscopic methods of the binding of copper in both oxidation states to R1 and R3 peptides, which contain one and two histidine residues, respectively. We also evaluate how the redox cycling of copper bound to tau peptides can mediate oxidation that can potentially target exogenous substrates such as neuronal catecholamines. The resulting quinone oxidation products undergo oligomerization and can competitively give post-translational peptide modifications yielding catechol adducts at amino acid residues. The presence of His–His tandem in the R3 peptide strongly influences both the binding of copper and the reactivity of the resulting copper complex. In particular, the presence of the two adjacent histidines makes the copper­(I) binding to R3 much stronger than in R1. The copper–R3 complex is also much more active than the copper–R1 complex in promoting oxidative reactions, indicating that the two neighboring histidines activate copper as a catalyst in molecular oxygen activation reactions.

Copper and zinc isotopic excursions in the human brain affected by Alzheimer's disease

“…An additional effect is the binding of copper and zinc to tau tangles 26 . Cu + can bind strongly to histidine residues of the tau proteins, 26 which would be enriched in the light isotope compared to normal brains (Cu 2+ bound to cysteine) and would enhance the effect seen with Aβ aggregation. On the other hand, Zn 2+ can bind to histidine in tau proteins, 27 which would therefore be isotopically heavier than normal brain.…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…Abbreviations: NH2: N-terminal amine, N Im : Nitrogen of imidazole ring of a His; N -: Nitrogen of an amidate; N: any nitrogen of unknown ligand. Review 668 and References [678][679][680] . The authors design the Figure.…”

Novel Perspective on Alzheimer’s Disease Treatment: Rosmarinic Acid Molecular Interplay with Copper(II) and Amyloid β

“…Both tau and Aβ proteins are able to bind copper ions [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. This interaction has a strong impact on two key events of AD: (i) it influences the aggregation pathways of Aβ and (ii) it leads to the formation of catalytic generation of reactive oxygen species (ROSs).…”