Origin of metastable oligomers and their effects on amyloid fibril self-assembly

摘要: Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature numerous neurodegenerative and non-neuropathic disorders. Frequently large populations small globular oligomers (gOs) curvilinear (CFs) precede the formation late-stage (RFs), have been implicated in toxicity. Yet our understanding origin these metastable oligomers, role as on-pathway precursors or off-pathway competitors, effects on self-assembly remains incomplete. Using two unrelated proteins, amyloid-β lysozyme, we find that gO/CF formation, analogous to micelle by surfactants, delineated “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates sigmoidal kinetics nucleated polymerization. Upon crossing becomes biphasic responsible for lag-free initial phase, followed second upswing dominated RF nucleation growth. lag periods below expected, decrease power law monomer concentration. Surprisingly, build-up gO/CFs above COC causes progressive increase periods. Our results suggest are from confined condition-dependent distinct solubility, underlie transition and, most importantly, not only compete RFs shared monomeric growth substrate but actively inhibit