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Sub-stoichiometric Hsp104 regulates the genesis and persistence of self-replicable amyloid seeds of a yeast prion protein

The prion-like self-perpetuating conformational conversion is involved in both transmissible neurodegenerative diseases and non-Mendelian inheritance traits. The transmissibility of amyloid-like aggregates is dependent on the stoichiometry of chaperones such as heat shock proteins. To provide the mechanistic underpinning of the generation and persistence of prefibrillar amyloid seeds that are critical for the prion-like propagation, we studied the effect of Hsp104 disaggregase on the assembly mechanism of a yeast prion determinant of Saccharomyces cerevisiae Sup35. At low sub-stoichiometric concentrations, Hsp104 exhibits a dual role and considerably accelerates the formation of seeding-competent prefibrillar amyloids by shortening the lag phase but also prolongs their persistence by introducing unusual kinetic halts and delaying their conversion into matured fibers. Hsp104-mediated amyloid species comprise a more ordered packing and display an enhanced autocatalytic self-templating ability compare to amyloids formed without Hsp104. Our findings underscore the key functional and pathological roles of sub-stoichiometric chaperones in prion-like propagation.