Chaperone proteins — the most disordered among all protein groups — help RNAs fold into their functional structure by destabilizing misfolded configurations or stabilizing the functional ones. But disentangling the mechanism underlying RNA chaperoning is challenging, mostly due to inherent disorder of the chaperones and the transient nature of their interactions with RNA. In particular, it is unclear how specific the interactions are and what role is played by amino acid charge and polarity patterns. Here, we address these questions in the RNA chaperone StpA. By adapting direct coupling analysis (DCA) to treat in tandem sequences written in two alphabets, nucleotides and amino acids, we could analyze StpA-RNA interactions and identify a two-pronged mechanism: StpA disrupts specific positions in the group I intron while globally and loosely binding to the entire structure. Moreover, the interaction is governed by the charge pattern: negatively charged regions in the destabilizing StpA N-terminal affect a few specific positions in the RNA, located in stems and in the pseudoknot. In contrast, positive regions in the C-terminal contain strongly coupled amino acids that promote non-specific or weakly-specific binding to the RNA. The present study opens new avenues to examine the functions of disordered proteins and to design disruptive proteins based on their charge patterns.
αβDCA method identifies unspecific binding but specific disruption of the group I intron by the StpA chaperone