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

A. Cléry, M. Krepl, CKX. Nguyen, A. Moursy, H. Jorjani, M. Katsantoni, M. Okoniewski, N. Mittal, M. Zavolan, J. Sponer, FH. Allain

. 2021 ; 12 (1) : 428. [pub] 20210118

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21011591

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.

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$a The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.
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$a Krepl, Miroslav $u Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 65, Brno, Czech Republic
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$a Nguyen, Cristina K X $u Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
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$a Moursy, Ahmed $u Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
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$a Okoniewski, Michal $u Scientific IT Services, ETH Zurich, Zurich, Switzerland
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$a Mittal, Nitish $u Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland
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$a Sponer, Jiri $u Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 65, Brno, Czech Republic
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$a Allain, Frédéric H-T $u Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland. allain@mol.biol.ethz.ch
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