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

• Published in: Journal of the American Chemical Society Vol. 143; no. 20; pp. 7839 - 7851
• Main Authors: Dregni, Aurelio J, Wang, Harrison K, Wu, Haifan, Duan, Pu, Jin, Jia, DeGrado, William F, Hong, Mei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.05.2021
• Subjects: amino acid sequences; heparin; Humans; nuclear magnetic resonance spectroscopy; Nuclear Magnetic Resonance, Biomolecular; patients; post-translational modification; protective effect; Protein Conformation, beta-Strand; tau Proteins - chemistry
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.1c03314

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 vivo may thus play an important role in the progression of tauopathies.