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

Antoine Cléry (), Miroslav Krepl, Cristina K. X. Nguyen, Ahmed Moursy, Hadi Jorjani, Maria Katsantoni, Michal Okoniewski, Nitish Mittal, Mihaela Zavolan, Jiri Sponer and Frédéric H.-T. Allain ()
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Antoine Cléry: Institute of Biochemistry, ETH Zurich
Miroslav Krepl: Institute of Biophysics of the Czech Academy of Sciences
Cristina K. X. Nguyen: Institute of Biochemistry, ETH Zurich
Ahmed Moursy: Institute of Biochemistry, ETH Zurich
Hadi Jorjani: University of Basel
Maria Katsantoni: University of Basel
Michal Okoniewski: Scientific IT Services, ETH Zurich
Nitish Mittal: University of Basel
Mihaela Zavolan: University of Basel
Jiri Sponer: Institute of Biophysics of the Czech Academy of Sciences
Frédéric H.-T. Allain: Institute of Biochemistry, ETH Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20481-w

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