The extracellular chaperone clusterin potently inhibits human lysozyme amyloid formation by interacting with prefibrillar species

We have studied the effects of the extracellular molecular chaperone,
clusterin, on the in vitro aggregation of mutational variants of human
lysozyme, including one associated with familial amyloid disease. The
aggregation of the amyloidogenic variant I56T is inhibited significantly at
clusterin to lysozyme ratios as low as 1:80 (i.e. one clusterin molecule per 80
lysozyme molecules). Experiments indicate that under the conditions where
inhibition of aggregation occurs, clusterin does not bind detectably to the
native or fibrillar states of lysozyme, or to the monomeric transient
intermediate known to be a key species in the aggregation reaction. Rather,
it seems to interact with oligomeric species that are present at low concentrations
during the lag (nucleation) phase of the aggregation reaction.
This behavior suggests that clusterin, and perhaps other extracellular
chaperones, could have a key role in curtailing the potentially pathogenic
effects of the misfolding and aggregation of proteins that, like lysozyme, are
secreted into the extracellular environment.