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082 _ _ |a 600
100 1 _ |a Majewski, Jaroslaw
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245 _ _ |a Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
260 _ _ |a [London]
|c 2020
|b Macmillan Publishers Limited, part of Springer Nature
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520 _ _ |a The aggregation of the intrinsically disordered tau protein into highly ordered β-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 ~ 40 proteins misfolded in a β-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 β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Intrinsically Disordered Proteins: chemistry
|2 MeSH
650 _ 2 |a Intrinsically Disordered Proteins: genetics
|2 MeSH
650 _ 2 |a Lipid Bilayers: chemistry
|2 MeSH
650 _ 2 |a Protein Conformation, beta-Strand
|2 MeSH
650 _ 2 |a Protein Folding
|2 MeSH
650 _ 2 |a Protein Multimerization
|2 MeSH
650 _ 2 |a tau Proteins: chemistry
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
700 1 _ |a Jones, Emmalee M.
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700 1 _ |a Vander Zanden, Crystal M.
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700 1 _ |a Biernat, Jacek
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700 1 _ |a Mandelkow, Eckhard
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700 1 _ |a Chi, Eva Y.
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773 _ _ |a 10.1038/s41598-020-70208-6
|g Vol. 10, no. 1, p. 13324
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856 4 _ |u https://www.nature.com/articles/s41598-020-70208-6
856 4 _ |u https://pub.dzne.de/record/153393/files/DZNE-2020-01390.pdf
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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