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@ARTICLE{Majewski:452699,
author = {Majewski, Jaroslaw and Jones, Emmalee M. and Vander Zanden,
Crystal M. and Biernat, Jacek and Mandelkow, Eckhard and
Chi, Eva Y.},
title = {{L}ipid membrane templated misfolding and self-assembly of
intrinsically disordered tau protein},
journal = {Scientific reports},
volume = {10},
number = {1},
issn = {2045-2322},
address = {[London]},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {PUBDB-2020-04826},
pages = {13324},
year = {2020},
abstract = {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.},
cin = {DOOR ; HAS-User},
ddc = {600},
cid = {I:(DE-H253)HAS-User-20120731},
pnm = {899 - ohne Topic (POF3-899)},
pid = {G:(DE-HGF)POF3-899},
experiment = {EXP:(DE-H253)D-BW1-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32770092},
UT = {WOS:000561428200001},
doi = {10.1038/s41598-020-70208-6},
url = {https://bib-pubdb1.desy.de/record/452699},
}