%0 Journal Article
%A Hasecke, Filip
%A Miti, Tatiana
%A Perez, Carlos
%A Barton, Jeremy
%A Schölzel, Daniel
%A Gremer, Lothar
%A Grüning, Clara S. R.
%A Matthews, Garrett
%A Meisl, Georg
%A Knowles, Tuomas P. J.
%A Willbold, Dieter
%A Neudecker, Philipp
%A Heise, Henrike
%A Ullah, Ghanim
%A Hoyer, Wolfgang
%A Muschol, Martin
%T Origin of metastable oligomers and their effects on amyloid fibril self-assembly
%J Chemical science
%V 9
%N 27
%@ 2041-6539
%C Cambridge
%I RSC
%M FZJ-2018-07275
%P 5937 - 5948
%D 2018
%X Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30079208
%U <Go to ISI:>//WOS:000438391900009
%R 10.1039/C8SC01479E
%U https://juser.fz-juelich.de/record/858389