Structure of the nonhelical filament of the Alzheimer’s disease tau core

Abstract

The microtubule-associated protein tau aggregates into neurofibrillary tangles in Alzheimer’s disease (AD). The main type of aggregates, the paired helical filaments (PHF), incorporate about 20% of the full-length protein into the rigid core. Recently, cryo-electron microscopy data showed that a protease-resistant fragment of tau (residues 297–391) self-assembles in vitro in the presence of divalent cations to form twisted filaments whose molecular structure resembles that of AD PHF tau [S. Lövestam et al., Elife 11 , e76494 (2022)]. To investigate whether this tau construct is uniquely predisposed to this morphology and structure, we fibrillized tau (297–391) under the reported conditions and determined its structure using solid-state NMR spectroscopy. Unexpectedly, the protein assembled predominantly into nontwisting ribbons whose rigid core spans residues 305–357. This rigid core forms a β-arch that turns at residues 322 CGS 324 . Two protofilaments stack together via a long interface that stretches from G323 to I354. Together, these two protofilaments form a four-layered β-sheet core whose sidechains are stabilized by numerous polar and hydrophobic interactions. This structure gives insight into the fibril morphologies and molecular conformations that can be adopted by this protease-resistant core of AD tau under different pH and ionic conditions.

Modulation of Primary and Secondary Processes in Tau Fibril Formation by Salt-Induced Dynamics

“…It is also worth noting that the concentration of the protein is important in determining the type of structure formed. Recent Cryo-EM and solid-state NMR studies suggest that tau 297–391 construct can form filaments with nonhelical structures, distinct from those found in Alzheimer’s disease when incubated with MgCl 2 . , However, the cryo-EM study showed that only when 2 mg/mL of protein was employed, around 90% of filamentous structures resembling PHF associated with Alzheimer’s disease (AD) were obtained, while higher concentration of protein produces fibrils which are dissimilar to ex vivo AD filaments . Therefore, in our study, we used ∼2 mg/mL (250 μM) protein for all experiments.…”