Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein

The aggregation of the intrinsically disordered tau protein into highly ordered {beta}-sheet fibrils is implicated in many neurodegenerative disorders. Fibrillation mechanism remains unresolved, particularly early events that trigger tau misfolding and assembly. We investigated the role membrane plays in modulating aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation mutant hTau40/3Epi. Despite being charged and soluble, tau proteins were also highly surface active and favorably interacted with anionic, but not zwitterionic, lipid monolayer at the air/water interface. Membrane binding induced macroscopic tau phase separation and {beta}-sheet-rich tau oligomer formation. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein taus inherent surface activity and favorable electrostatic interactions drive tau-membrane association, inducing tau phase separation that is accompanied by misfolding and self-assembly of disordered tau into {beta}-sheet-rich oligomers, which subsequently seed fibrillation and deposition into diseased tissues.