Metal ions control amyloid catalysis

Pathological amyloids, such as those formed by the protein α-synuclein in Parkinson's disease, have recently been shown to catalyze hydrolysis of ester and phosphoester bonds in vitro. Here, we report that this activity is modulated by divalent metal ions copper (Cu(II)) and zinc (Zn(II)). Specifically, α-synuclein amyloids formed in the presence of Zn(II) are catalytically inactive towards dephosphorylation of adenosine triphosphate (ATP) and cannot bind a fluorescent analog of ATP. In contrast, amyloids formed in the presence of Cu(II) retain catalytic activity towards ATP that is comparable to that of amyloids formed without metal ions. Amyloids of the α-synuclein variant with histidine at position 50 replaced by alanine (H50A) are inactive in catalyzing ATP hydrolysis independent of Zn(II); however, when these amyloids are formed in the presence of Cu(II), catalytic activity and ATP binding is restored. For lipase activity on a model substrate, both wild-type and H50A α-synuclein amyloids are catalytically active regardless of Cu(II), whereas amyloids of both variants formed in the presence of Zn(II) exhibit no such activity. In sharp contrast, hydrolysis of para-nitrophenyl acetate (pNPA) is insensitive to both metal ions and H50A mutation in the amyloids. Given the common occurrence of metal ion dysregulation in neurodegenerative disorders, and the propensity of many amyloidogenic proteins to bind metal ions, our findings imply that amyloid catalytic activity may be modulated by metal ions in vivo.