Pseudo-Phosphorylated Tau Forms Paired Helical Filaments in the Presence of High-Curvature Cholesterol-Containing Lipid Membranes
Name
nihms-2090415.pdf
Description
Accepted version
Size
3.39 MB
Format
Adobe PDF
Checksum (MD5)
dc30c3703457c1d31128c7a29e7bd08b
Author(s)
El Mammeri, Nadia
Duan, Pu
Hong, Mei
Date Issued
January 9, 2025
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Pseudo-Phosphorylated Tau Forms Paired Helical Filaments in the Presence of High-Curvature Cholesterol-Containing Lipid Membranes. Nadia El Mammeri, Pu Duan, and Mei Hong. Journal of the American Chemical Society 2025 147 (3), 2510-2522.
Version
Author's final manuscript
Abstract
The tau protein misfolds in neurodegenerative diseases such as Alzheimer's disease (AD). These pathological tau aggregates are associated with neuronal membranes, but molecular structural information about how disease-like tau fibrils interact with the lipid membrane is scarce. Here, we use solid-state NMR to investigate the structure of a tau construct bearing four AD-relevant phospho-mimetic mutations (4E tau) with cholesterol-containing high-curvature lipid membranes, which mimic the membrane of synaptic vesicles in neurons. We show that 4E tau adopts the AD paired helical filament (PHF) fold in the presence of the membrane at high protein concentrations. Moreover, it inserts into the membrane-water interface with an orientation that suggests possible bridging of multiple lipid vesicles. At lower protein concentrations, moderate chemical shift changes are observed, indicating a perturbation of the PHF structure by the lipids. Removal of the phospho-mimetic mutations led to a qualitatively different β-sheet conformation. These results indicate that posttranslational modifications impact the tau fibril structure more strongly than lipid membranes, but the membrane modulates the conformational equilibria of the aggregates.
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1021/jacs.4c13772
