ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1

ALS-causing C71G-hPFN1 coexists in both folded and unfolded states, while nascent hSOD1 is unfolded. So far, the mechanisms underlying their ALS-triggering potential remain enigmatic. Here we show by NMR that ATP completely converts C71G-hPFN1 into the folded state at a 1:2 ratio, while inducing nascent hSOD1 into two co-existing states at a 1:8 ratio. Surprisingly, the inducing capacity of ATP comes from its triphosphate, but free triphosphate triggers aggregation. The inducing capacity ranks as: ATP ATPγP > ADP AMP-PNP AMP-PCP = PP, while AMP, adenosine, P_i, and NaCl show no conversion. Mechanistically, ATP and triphosphate appear to enhance the intrinsic folding capacity encoded in the sequences, as unveiled by comparing conformations and dynamics of ATP- and Zn^2+-induced hSOD1 folded states. Our study provides a mechanism for the finding that some single-cell organisms employ polyphosphates as primordial chaperones, and sheds light on the enigma of age-related onset of familial ALS and risk increase of neurodegenerative diseases.