Pathological amyloids, such as those formed by α-synuclein in Parkinson’s disease, were recently shown to catalyze hydrolysis of ester and phosphoester model substrates as well as the universal energy molecule adenosine triphosphate (ATP) in vitro. We here report that amyloid-mediated ATP hydrolysis is shaped by both structural features and divalent metal ions. Using cryo-EM, we show that α-synuclein amyloids in the presence of ATP adopt a modified type-1A fold in which residues 16-22 form an additional β-strand that encloses ATP within a lysine-rich cavity. Positively charged residues lining this cavity are essential for catalysis, as single-point substitutions at these positions reduce amyloid-mediated ATP hydrolysis. In addition, metal ion incorporation into α-synuclein amyloids modulates ATP hydrolysis activity: amyloids formed in the presence of Zn(II) are inactive toward ATP hydrolysis, whereas amyloids formed in the presence of Cu(II) preserve catalytic activity and, for inactive His50Ala α-synuclein amyloids, restore catalytic activity. Our findings demonstrate that α-synuclein amyloid catalysis emerges from a structurally defined cavity enriched in lysine residues, and the catalytic outcome can be dynamically regulated by metal ions. The interplay between amyloid architecture, metal ion incorporation, and catalytic activity suggests a pathological mechanism in which amyloids drive metabolic collapse and metal ion imbalance, both being hallmarks of neurodegenerative disease.
Buratti et al. (Sun,) studied this question.