Pseudo-Phosphorylated Tau Forms Paired Helical Filaments in the Presence of High-Curvature Cholesterol-Containing Lipid Membranes

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.