TY  - JOUR
AU  - Perez, Carlos
AU  - Miti, Tatiana
AU  - Hasecke, Filip
AU  - Meisl, Georg
AU  - Hoyer, Wolfgang
AU  - Muschol, Martin
AU  - Ullah, Ghanim
TI  - Mechanism of Fibril and Soluble Oligomer Formation in Amyloid Beta and Hen Egg White Lysozyme Proteins
JO  - The journal of physical chemistry  / B B, Condensed matter, materials, surfaces, interfaces & biophysical
VL  - 123
IS  - 27
SN  - 1520-5207
CY  - Washington, DC
PB  - Soc.
M1  - FZJ-2020-00242
SP  - 5678 - 5689
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31246474
UR  - <Go to ISI:>//WOS:000475540400002
DO  - DOI:10.1021/acs.jpcb.9b02338
UR  - https://juser.fz-juelich.de/record/872764
ER  -