Origin of Metastable Oligomers and their Effects on Amyloid Fibril Self-Assembly

Authors

Filip Hasecke, Heinrich-Heine-Universität
Tatiana Miti, University of South FloridaFollow
Carlos Perez, University of South FloridaFollow
Jeremy Barton, University of South FloridaFollow
Daniel Schölzel, Heinrich-Heine-Universität
Lothar Gremer, Heinrich-Heine-Universität
Clara S. R. Grüning, Heinrich-Heine-Universität
Garrett Matthews, University of South FloridaFollow
Georg Meisl, University of Cambridge
Tuomas P. J. Knowles, University of Cambridge
Ghanim Ullah, University of South FloridaFollow
Martin M. Muschol, University of South FloridaFollow

Document Type

Article

Publication Date

2018

Digital Object Identifier (DOI)

https://doi.org/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.

Comments

Complete list of authors: Dieter Willbold, Phillip Neudeckerm Henrike Heise, Wolfgang Hoyer

Rights Information

This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Chemical Science, v. 9, p. 5937-5948

Scholar Commons Citation

Hasecke, Filip; Miti, Tatiana; Perez, Carlos; Barton, Jeremy; Schölzel, Daniel; Gremer, Lothar; Grüning, Clara S. R.; Matthews, Garrett; Meisl, Georg; Knowles, Tuomas P. J.; Ullah, Ghanim; and Muschol, Martin M., "Origin of Metastable Oligomers and their Effects on Amyloid Fibril Self-Assembly" (2018). Physics Faculty Publications. 37.
https://digitalcommons.usf.edu/phy_facpub/37