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000858389 1001_ $$0P:(DE-HGF)0$$aHasecke, Filip$$b0
000858389 245__ $$aOrigin of metastable oligomers and their effects on amyloid fibril self-assembly
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000858389 520__ $$aAssembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.
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000858389 7001_ $$0P:(DE-HGF)0$$aMiti, Tatiana$$b1
000858389 7001_ $$0P:(DE-HGF)0$$aPerez, Carlos$$b2
000858389 7001_ $$0P:(DE-HGF)0$$aBarton, Jeremy$$b3
000858389 7001_ $$0P:(DE-Juel1)165604$$aSchölzel, Daniel$$b4$$ufzj
000858389 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b5
000858389 7001_ $$0P:(DE-HGF)0$$aGrüning, Clara S. R.$$b6
000858389 7001_ $$0P:(DE-HGF)0$$aMatthews, Garrett$$b7
000858389 7001_ $$00000-0002-6562-7715$$aMeisl, Georg$$b8
000858389 7001_ $$00000-0002-0016-3008$$aKnowles, Tuomas P. J.$$b9
000858389 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b10
000858389 7001_ $$0P:(DE-Juel1)144510$$aNeudecker, Philipp$$b11
000858389 7001_ $$0P:(DE-Juel1)132002$$aHeise, Henrike$$b12
000858389 7001_ $$0P:(DE-HGF)0$$aUllah, Ghanim$$b13
000858389 7001_ $$0P:(DE-Juel1)166306$$aHoyer, Wolfgang$$b14$$eCorresponding author
000858389 7001_ $$00000-0002-6488-0049$$aMuschol, Martin$$b15$$eCorresponding author
000858389 773__ $$0PERI:(DE-600)2559110-1$$a10.1039/C8SC01479E$$gVol. 9, no. 27, p. 5937 - 5948$$n27$$p5937 - 5948$$tChemical science$$v9$$x2041-6539$$y2018
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