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. 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.

Biomolecular NMR Spectroscopy Platform ETH Zurich Zurich Switzerland

Computational and Systems Biology Biozentrum University of Basel Basel Switzerland

Department of Biology Institute of Biochemistry ETH Zurich Zurich Switzerland

Institute of Biophysics of the Czech Academy of Sciences Kralovopolska 135 612 65 Brno Czech Republic

Scientific IT Services ETH Zurich Zurich Switzerland

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How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study

Spontaneous binding of single-stranded RNAs to RRM proteins visualized by unbiased atomistic simulations with a rescaled RNA force field