TiO2 Nanoparticles Catalyze Oxidation of Huntingtin Exon 1‑Derived Peptides Impeding Aggregation: A Quantitative NMR Study of Binding and Kinetics
journal contributionposted on 12.12.2018, 00:00 by Alberto Ceccon, Vitali Tugarinov, G. Marius Clore
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 (httNT) or with (httNTQ10) a ten-residue C-terminal polyglutamine tract, is investigated by NMR spectroscopy. TiO2 nanoparticles decrease aggregation of httNTQ10 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 httNT 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.
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binding kineticsaggregation-incompetent peptidehydrogen peroxideKinetics Polyglutamine expansionhtt NThuntingtin peptidesTiO 2 nanoparticleshuntingtin protein resultsBindingN-terminal domainUV irradiationN-terminal regionNMR dataTiO 2 nanoparticles decrease aggregationQuantitative NMR Studystate exchange saturation transferintracellular aggregatesHuntingtonhtt NT Q 10lifetime lineneurodegenerative conditionhuntingtin proteinnonaggregating htt NTten-residue C-terminal polyglutamine tract15 Noxidation agentMet 7methionine oxidationNMR spectroscopyN-terminal amphiphilic domainTiO 2 Nanoparticles Catalyze Oxidation