pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers

摘要: Amyloid disorders cause debilitating illnesses through the formation of toxic protein aggregates. The mechanisms amyloid toxicity and nature species responsible for mediating cellular dysfunction remain unclear. Here, using β2-microglobulin (β2m) as a model system, we show that disruption membranes by fibrils is caused molecular shedding membrane-active oligomers in process dependent on pH. Using thioflavin T (ThT) fluorescence, NMR, EM fluorescence correlation spectroscopy (FCS), fibril disassembly at pH 6.4 results nonnative spherical disrupt synthetic membranes. By contrast, dissociation 7.4 nontoxic, native monomers. Chemical cross-linking or interaction with hsp70 increases kinetic stability decreases their capacity to membrane dysfunction. demonstrate how can modulate deleterious effects preformed aggregates suggest why endocytic trafficking acidic compartments may be key factor disease.