Adenosine Triphosphate Promotes Amyloid Formation of α-Synuclein in a Concentration-Dependent Manner

Adenosine triphosphate (ATP) is an essential molecule involved in various biological reactions in vivo. It has been reported that ATP acts as a hydrotrope, dissolving the hydrophobic molecules in aqueous solution. Previously, we reported that polyphosphates, including triphosphate, significantly accelerated amyloid formation under ultrasonication. In this study, adenosine nucleotides, including AMP, ADP, and ATP, were used to investigate the mechanism of amyloid formation of α-synuclein (αSyn) under ultrasonication at various adenosine nucleotide concentrations. As a result, amyloid formation was accelerated at two distinct concentration regions of adenosine nucleotides, i.e., relatively low and high via the charge-charge interactions and salting-out effect in the Hofmeister series, respectively, at neutral pH. A similar concentration-dependent amyloid formation was also observed with polyphosphates possessing corresponding phosphate chain lengths. At acidic pH, ATP accelerated the formation of both amyloid fibrils and amorphous aggregates of αSyn, β₂-microglobulin, and insulin via charge-charge interaction. Moreover, under acidic conditions, ATP might induce conformational transitions from the unfolded monomeric state to a molten globule-like state. These findings suggest that ATP functions as a salt, stabilizing compact conformers, including the native-like structure and amyloid fibril via intra- and intermolecular interactions, respectively. ATP may trigger amyloid formation by disrupting the supersaturated state above the thermodynamic solubility.