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000153393 0247_ $$2doi$$a10.1038/s41598-020-70208-6
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000153393 037__ $$aDZNE-2020-01390
000153393 041__ $$aEnglish
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000153393 1001_ $$aMajewski, Jaroslaw$$b0
000153393 245__ $$aLipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
000153393 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2020
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000153393 520__ $$aThe aggregation of the intrinsically disordered tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the lipid membrane plays in modulating the aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the tau proteins were also highly surface active and favorably interacted with anionic lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of ~ 40 proteins misfolded in a β-sheet conformation at the membrane surface, as detected by in situ synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau’s inherent surface activity and favorable interactions with anionic lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.
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000153393 650_2 $$2MeSH$$aHumans
000153393 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: chemistry
000153393 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: genetics
000153393 650_2 $$2MeSH$$aLipid Bilayers: chemistry
000153393 650_2 $$2MeSH$$aProtein Conformation, beta-Strand
000153393 650_2 $$2MeSH$$aProtein Folding
000153393 650_2 $$2MeSH$$aProtein Multimerization
000153393 650_2 $$2MeSH$$atau Proteins: chemistry
000153393 650_2 $$2MeSH$$atau Proteins: genetics
000153393 7001_ $$aJones, Emmalee M.$$b1
000153393 7001_ $$aVander Zanden, Crystal M.$$b2
000153393 7001_ $$0P:(DE-2719)2810342$$aBiernat, Jacek$$b3$$udzne
000153393 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b4$$udzne
000153393 7001_ $$0P:(DE-HGF)0$$aChi, Eva Y.$$b5$$eCorresponding author
000153393 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-020-70208-6$$gVol. 10, no. 1, p. 13324$$n1$$p13324$$tScientific reports$$v10$$x2045-2322$$y2020
000153393 8564_ $$uhttps://www.nature.com/articles/s41598-020-70208-6
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