ATP modulates self-perpetuating conformational conversion generating structurally distinct yeast prion amyloids that...

Area of Science:

• Biochemistry
• Molecular Biology
• Neurodegenerative Diseases

Background:

• Prion-like protein misfolding into amyloid aggregates is linked to neurodegenerative diseases and non-Mendelian inheritance.
• Adenosine triphosphate (ATP) indirectly influences amyloid dynamics via molecular chaperones involved in protein homeostasis.

Purpose of the Study:

• To investigate the direct role of ATP, independent of chaperones, in modulating amyloid formation, dissolution, and prion-like transmission.
• To elucidate the concentration-dependent mechanisms by which ATP affects amyloid aggregation and seeding.

Main Methods:

• In vitro studies using the yeast prion domain (NM domain of Saccharomyces cerevisiae Sup35) and a human protein with a yeast prion-like domain.
• Analysis of ATP's effect on amyloid formation, phase separation, disaggregation, and autocatalytic amplification.
• Investigation of ATP-bound aggregate structure and fragmentation characteristics.

Main Results:

• ATP directly accelerates NM aggregation at high physiological concentrations and promotes phase separation-mediated aggregation of human prion-like proteins.
• ATP disaggregates preformed NM fibrils in a dose-independent manner, producing no seeding-competent oligomers.
• High ATP concentrations limit seeding by forming compact ATP-bound fibrils with reduced fragmentation, while low ATP concentrations generate structurally distinct, seeding-inefficient amyloids.

Conclusions:

• ATP acts as a chemical chaperone, directly regulating amyloid formation, dissolution, and prion-like transmission in a concentration-dependent manner.
• ATP's distinct effects on aggregate structure and fragmentation offer mechanistic insights into controlling amyloid propagation.
• These findings highlight ATP's crucial role in preventing prion-like amyloid transmission.