دورية
Inclusion of the C-Terminal Domain in the β-Sheet Core of Heparin-Fibrillized Three-Repeat Tau Protein Revealed by Solid-State Nuclear Magnetic Resonance Spectroscopy
| العنوان: | Inclusion of the C-Terminal Domain in the β-Sheet Core of Heparin-Fibrillized Three-Repeat Tau Protein Revealed by Solid-State Nuclear Magnetic Resonance Spectroscopy |
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| المؤلفون: | Dregni, Aurelio J., Wang, Harrison K., Wu, Haifan, Duan, Pu, Jin, Jia, DeGrado, William F., Hong, Mei |
| المصدر: | Journal of the American Chemical Society; May 2021, Vol. 143 Issue: 20 p7839-7851, 13p |
| مستخلص: | Many neurodegenerative diseases such as Alzheimer’s disease are characterized by pathological β-sheet filaments of the tau protein, which spread in a prion-like manner in patient brains. To date, high-resolution structures of tau filaments obtained from patient brains show that the β-sheet core only includes portions of the microtubule-binding repeat domains and excludes the C-terminal residues, indicating that the C-terminus is dynamically disordered. Here, we use solid-state NMR spectroscopy to identify the β-sheet core of full-length 0N3R tau fibrillized using heparin. Assignment of 13C and 15N chemical shifts of the rigid core of the protein revealed a single predominant β-sheet conformation, which spans not only the R3, R4, R′ repeats but also the entire C-terminal domain (CT) of the protein. This massive β-sheet core qualitatively differs from all other tau fibril structures known to date. Using long-range correlation NMR experiments, we found that the R3 and R4 repeats form a β-arch, similar to that seen in some of the brain-derived tau fibrils, but the R1 and R3 domains additionally stack against the CT, reminiscent of previously reported transient interactions of the CT with the microtubule-binding repeats. This expanded β-sheet core structure suggests that the CT may have a protective effect against the formation of pathological tau fibrils by shielding the amyloidogenic R3 and R4 domains, preventing side-on nucleation. Truncation and post-translational modification of the CT in vivomay thus play an important role in the progression of tauopathies. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00027863 15205126 |
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| DOI: | 10.1021/jacs.1c03314 |