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 = ATPP = PPP > ADP = AMP-PNP = AMP-PCP = PP, while AMP, adenosine, P, 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 Zn²⁺-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.