How the structure of SRSF1 RRM1 bound to RNA led to a variant that activates SMN2 exon7 splicing
A recent Nature Communications paper by the Allain (ETH Zurich), Zavolan (Uni Basel) and Sponer groups identified a novel mode of interaction of the splicing regulator SRSF1 with RNA and found a structure-based mutant that restores the deficient splicing of SMN exon7 responsible for Spinal Muscular Atrophy.
The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. 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 SMN exon7 inclusion, a strategy that is used to cure Spinal Muscular Atrophy (SMA). Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.
Link to the paper in external page Nature Communications.