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

    Year: 2020

    Journal: Sci Rep, Volume 10, AUG 7

    Authors: Majewski, J; Jones, EM; Vander Zanden, CM; Biernat, J; Mandelkow, E; Chi, EY

    Organizations: National Science FoundationNational Science Foundation (NSF) [1150855]; Alzheimer's AssociationAlzheimer's Association [NIRG-09-132478]; UNM Research Allocation Committee; Oak Ridge Associated Universities Ralph E. Powe Junior Faculty Enhancement Award; NSF-IGERT program Integrative Nanoscience and Microsystems; NCI Alliance for Nanotechnology in Cancer; ASERT IRACDA [K12 GM088021]; NSFNational Science Foundation (NSF); Max-Planck-Society (Max-Planck-Unit for Structural Molecular Biology at DESY, Hamburg); German Center for Neurodegenerative Diseases (DZNE, Bonn)Helmholtz Association; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SPP-2191]

    The aggregation of the intrinsically disordered tau protein into highly ordered beta-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the lipid membrane plays in modulating the aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the tau proteins were also highly surface active and favorably interacted with anionic lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of similar to 40 proteins misfolded in a beta-sheet conformation at the membrane surface, as detected by in situ synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau's inherent surface activity and favorable interactions with anionic lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into beta-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.
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