Structure of the nonhelical filament of the Alzheimer’s disease tau core
Name
duan-et-al-2023-structure-of-the-nonhelical-filament-of-the-alzheimer-s-disease-tau-core.pdf
Description
Published version
Size
5.13 MB
Format
Adobe PDF
Checksum (MD5)
090e90bfa93f01c8dd3e7db9786d871f
Author(s)
Duan, Pu
Dregni, Aurelio J
Mammeri, Nadia El
Hong, Mei
Date Issued
September 27, 2023
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
P. Duan,A.J. Dregni,N.E. Mammeri, & M. Hong, Structure of the nonhelical filament of the Alzheimer’s disease tau core, Proc. Natl. Acad. Sci. U.S.A. 120 (44) e2310067120.
Version
Final published version
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 322CGS324. 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.
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.2310067120
