Monovalent Ionic Atmosphere Modulates the Selection of Suboptimal RNA Sequences by Splicing Factors’ RNA Recognition Motifs

The U2AF2 splicing factor is involved in the RNA recognition of the pre-mRNA poly-pyrimidine signaling sequence. This protein contains two RRM domains connected by a flexible linker, which ensure the preferential selection of a poly-uridine sequence over a poly-cytosine one. In this work, all-atom simulations provide insights into the U2AF2 recognition mechanism and on the features underlying its selectivity. Our outcomes show that U2AF2’s RNA recognition is driven by cooperative events modulated by RNA–protein and RNA–ion interactions. Stunningly, monovalent ions contribute to mediating the binding of the weakly binding polyC strand, thus contributing to the selection of suboptimal poly-pyrimidine tracts. This finding broadens our understanding of the diverse traits tuning splicing factors’ selectivity and adaptability to precisely handle and process diverse pre-mRNA sequences.