ATP modulates self-perpetuating conformational conversion generating structurally distinct yeast prion amyloids that limit autocatalytic amplification

Prion-like self-perpetuating conformational conversion of proteins into amyloid aggregates is associated with both trans-missible neurodegenerative diseases and non-Mendelian inher-itance. The cellular energy currency ATP is known to indirectly regulate the formation, dissolution, or transmission of amyloid-like aggregates by providing energy to the molecular chaperones that maintain protein homeostasis. In this work, we demonstrate that ATP molecules, independent of any chaperones, modulate the formation and dissolution of amyloids from a yeast prion domain (NM domain of Saccharomyces cerevisiae Sup35) and restricts autocatalytic amplification by controlling the amount of fragmentable and seeding-competent aggregates. ATP, at (high) physiological concentrations in the presence of Mg2+, kinetically accelerates NM aggregation. Interestingly, ATP also promotes phase separation-mediated aggregation of a human protein harboring a yeast prion-like domain. We also show that ATP disaggregates preformed NM fibrils in a dose-independent manner. Our results indicate that ATP-mediated disaggrega-tion, unlike the disaggregation by the disaggregase Hsp104, yields no oligomers that are considered one of the critical species for amyloid transmission. Furthermore, high concentrations of ATP delimited the number of seeds by giving rise to compact ATP-bound NM fibrils that exhibited nominal fragmentation by either free ATP or Hsp104 disaggregase to generate lower mo-lecular weight amyloids. In addition, (low) pathologically rele-vant ATP concentrations restricted autocatalytic amplification by forming structurally distinct amyloids that are found seeding inefficient because of their reduced beta-content. Our results pro-vide key mechanistic underpinnings of concentration -dependent chemical chaperoning by ATP against prion-like transmissions of amyloids.

Automated summary

Prion-like self-perpetuating conformational conversion of proteins into amyloid aggregates is influenced by ATP molecules, which can both accelerate aggregation and disaggregate preformed fibrils. ATP modulates the formation and dissolution of amyloids and restricts autocatalytic amplification by controlling the amount of fragmentable and seeding-competent aggregates. Furthermore, ATP can promote phase separation-mediated aggregation of proteins harboring prion-like domains. These findings provide important mechanistic insights into the concentration-dependent chemical chaperoning by ATP against prion-like transmissions of amyloids.