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.
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