TY  - JOUR
AU  - Hasecke, Filip
AU  - Miti, Tatiana
AU  - Perez, Carlos
AU  - Barton, Jeremy
AU  - Schölzel, Daniel
AU  - Gremer, Lothar
AU  - Grüning, Clara S. R.
AU  - Matthews, Garrett
AU  - Meisl, Georg
AU  - Knowles, Tuomas P. J.
AU  - Willbold, Dieter
AU  - Neudecker, Philipp
AU  - Heise, Henrike
AU  - Ullah, Ghanim
AU  - Hoyer, Wolfgang
AU  - Muschol, Martin
TI  - Origin of metastable oligomers and their effects on amyloid fibril self-assembly
JO  - Chemical science
VL  - 9
IS  - 27
SN  - 2041-6539
CY  - Cambridge
PB  - RSC
M1  - FZJ-2018-07275
SP  - 5937 - 5948
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30079208
UR  - <Go to ISI:>//WOS:000438391900009
DO  - DOI:10.1039/C8SC01479E
UR  - https://juser.fz-juelich.de/record/858389
ER  -