ATP is a cryptic binder of TDP-43 RRM domains to enhance stability and inhibit ALS/AD-associated fibrillation.

ATP is the universal energy currency for all cells but has cellular concentrations of 2-12 mM, much higher than required for its classic functions. RNA-recognition motif (RRM) constitutes one of the most abundant domains in eukaryotes and most heterogeneous nuclear ribonucleoproteins (hnRNP) contain RRM domains which not only mediate direct interactions with nucleic acids, but whose aggregation/fibrillation is the pathological hallmark of various human diseases. Here, by NMR and molecular docking, ATP has been decoded to bind TDP-43 two tandem RRM domains with distinctive types of interactions, thus resulting in diverse affinities. Most strikingly, the binding of ATP enhances thermodynamic stability of TDP-43 RRM domains and inhibits ALS-/AD-associated fibrillation. Together, ATP is a cryptic binder of RRM-containing proteins which generally safeguards functional phase separation from transforming into pathological aggregation/fibrillation associated with various diseases and ageing. Our study thus reveals a mechanism of ATP to control protein homeostasis by specific binding.