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@ARTICLE{Perez:872764,
author = {Perez, Carlos and Miti, Tatiana and Hasecke, Filip and
Meisl, Georg and Hoyer, Wolfgang and Muschol, Martin and
Ullah, Ghanim},
title = {{M}echanism of {F}ibril and {S}oluble {O}ligomer
{F}ormation in {A}myloid {B}eta and {H}en {E}gg {W}hite
{L}ysozyme {P}roteins},
journal = {The journal of physical chemistry / B B, Condensed matter,
materials, surfaces, interfaces $\&$ biophysical},
volume = {123},
number = {27},
issn = {1520-5207},
address = {Washington, DC},
publisher = {Soc.},
reportid = {FZJ-2020-00242},
pages = {5678 - 5689},
year = {2019},
abstract = {Assembly and deposition of insoluble amyloid fibrils with a
distinctive cross-β-sheet structure is the molecular
hallmark of amyloidogenic diseases affecting the central
nervous system as well as non-neuropathic amyloidosis.
Amyloidogenic proteins form aggregates via kinetic pathways
dictated by initial solution conditions. Often, early stage,
cytotoxic, small globular amyloid oligomers (gOs) and
curvilinear fibrils (CFs) precede the formation of
late-stage rigid fibrils (RFs). Growing experimental
evidence suggests that soluble gOs are off-pathway
aggregates that do not directly convert into the final stage
RFs. Yet, the kinetics of RFs aggregation under conditions
that either promote or suppress the growth of gOs remain
incompletely understood. Here we present a self-assembly
model for amyloid fibril formation in the presence and
absence of early stage off-pathway aggregates, driven by our
experimental results on hen egg white lysozyme (HewL) and
beta amyloid (Aβ) aggregation. The model reproduces a range
of experimental observations including the sharp boundary in
the protein concentration above which the self-assembly of
gOs occurs. This is possible when both primary and secondary
RFs nucleation rates are allowed to have a nonlinear
dependence on initial protein concentration, hinting toward
more complex prenucleation and RFs assembly scenarios.
Moreover, analysis of RFs lag period in the presence and
absence of gOs indicates that these off-pathway aggregates
have an inhibitory effect on RFs nucleation. Finally, we
incorporate the effect of an Aβ binding protein on the
aggregation process in the model that allows us to identify
the most suitable solution conditions for suppressing gOs
and RFs formation.},
cin = {ICS-6},
ddc = {530},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31246474},
UT = {WOS:000475540400002},
doi = {10.1021/acs.jpcb.9b02338},
url = {https://juser.fz-juelich.de/record/872764},
}