Structure of SRSF1 RRM1 bound to RNA reveals an unexpected pendular/bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing

The human prototypical SR protein SRSF1 is an oncoprotein that plays a pivotal role in RNA metabolism. Nevertheless, the mode of RNA recognition and the exact motif bound by this protein have still not been clearly characterized. SRSF1 contains two RNA recognition motifs (RRM1 and RRM2). We previously found that the pseudo-RRM (RRM2) of this protein interacted specifically with a GGA motif. Here, we determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN2 exon7 inclusion, a strategy that could be used to cure spinal muscular atrophy. Finally, a new SELEX experiment was performed with SRSF1 RRMs. It revealed that the flexible inter-RRM linker of SRSF1 allowed RRM1 to bind RNA on both sides of RRM2 binding site explaining the difficulty to derive a consensus binding sequence for this protein so far. In addition to reveal a new and unusual pendular/bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new vision on the mode of action of SRSF1 in cells.