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| 001 | 858389 | ||
| 005 | 20210129235937.0 | ||
| 024 | 7 | _ | |a 10.1039/C8SC01479E |2 doi |
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| 100 | 1 | _ | |a Hasecke, Filip |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a Origin of metastable oligomers and their effects on amyloid fibril self-assembly |
| 260 | _ | _ | |a Cambridge |c 2018 |b RSC |
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| 520 | _ | _ | |a 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. |
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| 700 | 1 | _ | |a Perez, Carlos |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Barton, Jeremy |0 P:(DE-HGF)0 |b 3 |
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| 700 | 1 | _ | |a Knowles, Tuomas P. J. |0 0000-0002-0016-3008 |b 9 |
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| 700 | 1 | _ | |a Ullah, Ghanim |0 P:(DE-HGF)0 |b 13 |
| 700 | 1 | _ | |a Hoyer, Wolfgang |0 P:(DE-Juel1)166306 |b 14 |e Corresponding author |
| 700 | 1 | _ | |a Muschol, Martin |0 0000-0002-6488-0049 |b 15 |e Corresponding author |
| 773 | _ | _ | |a 10.1039/C8SC01479E |g Vol. 9, no. 27, p. 5937 - 5948 |0 PERI:(DE-600)2559110-1 |n 27 |p 5937 - 5948 |t Chemical science |v 9 |y 2018 |x 2041-6539 |
| 856 | 4 | _ | |y OpenAccess |u https://juser.fz-juelich.de/record/858389/files/Origin%20of%20metastable%20oligomers%20and%20their%20effects%20on%20amyloid%20fibril%20self-assembly_2018.pdf |
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