TiO2 Nanoparticles Catalyze Oxidation of Huntingtin Exon 1-Derived Peptides Impeding Aggregation: A Quantitative NMR Study of Binding and Kinetics

Abstract

Polyglutamine expansion within the N-terminal region of the huntingtin protein results in the formation of intracellular aggregates responsible for Huntington's disease, a fatal neurodegenerative condition. The interaction between TiO₂ nanoparticles and huntingtin peptides comprising the N-terminal amphiphilic domain without (htt^NT) or with (htt^NTQ₁₀) a ten-residue C-terminal polyglutamine tract, is investigated by NMR spectroscopy. TiO₂ nanoparticles decrease aggregation of htt^NTQ₁₀ by catalyzing the oxidation of Met⁷ to a sulfoxide, resulting in an aggregation-incompetent peptide. The oxidation agent is hydrogen peroxide generated on the surface of the TiO₂ nanoparticles either by UV irradiation or at low steady-state levels in the dark. The binding kinetics of nonaggregating htt^NT to TiO₂ nanoparticles is characterized by quantitative analysis of ¹⁵N dark state exchange saturation transfer and lifetime line broadening NMR data. Binding involves a sparsely populated intermediate that experiences hindered rotational diffusion relative to the free state. Catalysis of methionine oxidation within the N-terminal domain of the huntingtin protein may potentially provide a strategy for delaying the onset of Huntington's disease.