αB-crystallin inhibits amyloidogenesis by disassembling aggregation nuclei

Amyloid formation is implicated in a range of neurodegenerative conditions including Alzheimers and Parkinsons diseases. The small heat-shock protein B-crystallin (BC) is associated with both, and directly inhibits amyloid formation in vitro and its toxicity in cells. Studying the mechanism of aggregation inhibition is challenging owing to sample heterogeneity and the dynamic nature of the process. Here, by means of NMR spectroscopy and chemical kinetics, we establish the mechanism by which the protein -lactalbumin aggregates and forms amyloid, and how this is inhibited by BC. In particular, we characterise the lifetime of the unstable aggregation nucleus, and determine that this species is specifically destabilised by BC. This mechanism allows the chaperone to delay the onset of aggregation, although it is overwhelmed on longer timescales. The methodology we present provides a mechanistic understanding of how BC reduces the toxicity of amyloids, and is widely applicable to other complex mixtures.