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.
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