Journal Article

FZJ-2018-07275

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Origin of metastable oligomers and their effects on amyloid fibril self-assembly

Hasecke, F. ; Miti, T. ; Perez, C. ; Barton, J. ; Schölzel, D.FZJ* ; Gremer, L.FZJ* ; Grüning, C. S. R. ; Matthews, G. ; Meisl, G. ; Knowles, T. P. J. ; Willbold, D.FZJ* ; Neudecker, P.FZJ* ; Heise, H.FZJ* ; Ullah, G. ; Hoyer, W. (Corresponding author)FZJ* ; Muschol, M. (Corresponding author)

2018
RSC Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/20474  doi:10.1039/C8SC01479E

Abstract: 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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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)

Appears in the scientific report 2018

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Database coverage:
; ; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; National-Konsortium ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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