ATP Hydrolysis by α-Synuclein Amyloids is Mediated by Enclosing β-Strand.

Pathological amyloids, like those formed by α-synuclein in Parkinson's disease, are recently found to catalyze the hydrolysis of model substrates in vitro. Here it is reported that the universal energy molecule ATP is another substrate for α-synuclein amyloid chemical catalysis. To reveal the underlying mechanism, the high-resolution cryo-EM structure of the amyloids in the presence of ATP is solved. The structure reveals a type 1A amyloid fold with an additional β-strand involving residues 16-22 that wraps around the ATP, creating an enclosed cavity at the interface of the protofilaments. Mutations of putative ATP-interacting residues in the cavity and the additional β-strand showed that replacing any one of Lys21, Lys23, Lys43, Lys45, and Lys60 with Ala reduced amyloid-mediated ATPase activity. High-resolution structural analysis of Lys21Ala α-synuclein amyloids in the presence of ATP reveals the same fold as wild-type α-synuclein amyloids but without the extra β-strand and with ATP oriented differently. It is concluded that positively-charged side chains, along with ordering of the N-terminal part into a β-strand, enclosing the cavity, are essential parameters governing ATP hydrolysis by α-synuclein amyloids. Amyloid-catalyzed ATP hydrolysis may hamper ATP-dependent rescue systems near amyloid deposits in vivo.