ATP binds nucleic-acid-binding domains beyond RRM fold

Abstract

It has remained a mystery why cells maintain ATP concentrations of 2-12 mM, much higher than required for its known functions, until ATP is decoded to act as a hydrotrope to non-specifically control protein homeostasis above 5 mM. Unexpectedly, our NMR studies further reveal that by specific binding, ATP also mediates liquid-liquid phase separation in a two-stage style and inhibits fibrillation of RRM domains of FUS and TDP-43, implying that ATP might have a second category of functions previously unknown. So can ATP also bind nucleic-acid-binding proteins without RRM fold? Here we characterized the interaction between ATP and SYNCRIP acidic domain (AcD), a non-canonical RNA-binding domain with no similarity to RRM fold in sequence and structure. The results reveal that ATP does bind AcD at physiologically-relevant concentrations with the affinity determinants generally underlying protein-nucleic acid interactions. Therefore, at concentrations above mM, ATP might bind most, if not all, nucleic-acid-binding proteins.

Keywords: Acidic domain (AcD); Adenosine triphosphate (ATP); Molecular docking; NMR spectroscopy; Non-canonical RNA-Binding domain; SYNCRIP (hnRNP Q).