期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 1, 页码 94-97出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b11441
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资金
- Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK029023] Funding Source: NIH RePORTER
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(NT)Q(10)) a ten residue C-terminal polyglutamine tract, is investigated by NMR spectroscopy. TiO2 nanoparticles decrease aggregation of htt(NT)Q(10) by catalyzing the oxidation of Met(7) 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 N-15 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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