Antoine Cléry1,2, Miroslav Krepl3, Cristina K X Nguyen4, Ahmed Moursy4, Hadi Jorjani5, Maria Katsantoni5, Michal Okoniewski6, Nitish Mittal5, Mihaela Zavolan5, Jiri Sponer3, Frédéric H-T Allain7. 1. Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland. aclery@mol.biol.ethz.ch. 2. Biomolecular NMR Spectroscopy Platform, ETH Zurich, Zurich, Switzerland. aclery@mol.biol.ethz.ch. 3. Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 65, Brno, Czech Republic. 4. Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland. 5. Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland. 6. Scientific IT Services, ETH Zurich, Zurich, Switzerland. 7. Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland. allain@mol.biol.ethz.ch.
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.
The human prototypical SR protein pan> class="Gene">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.
Authors: U R Monani; C L Lorson; D W Parsons; T W Prior; E J Androphy; A H Burghes; J D McPherson Journal: Hum Mol Genet Date: 1999-07 Impact factor: 6.150
Authors: Andrew M Jobbins; Sébastien Campagne; Robert Weinmeister; Christian M Lucas; Alison R Gosliga; Antoine Clery; Li Chen; Lucy P Eperon; Mark J Hodson; Andrew J Hudson; Frédéric H T Allain; Ian C Eperon Journal: EMBO J Date: 2021-11-15 Impact factor: 11.598
Authors: Anna Knörlein; Chris P Sarnowski; Tebbe de Vries; Moritz Stoltz; Michael Götze; Ruedi Aebersold; Frédéric H-T Allain; Alexander Leitner; Jonathan Hall Journal: Nat Commun Date: 2022-05-17 Impact factor: 17.694
Authors: C Cheng Kao; Yuchun Nie; Suping Ren; N Tilani T S De Costa; Rajendra K Pandey; Jin Hong; David B Smith; Julian A Symons; Leonid Beigelman; Lawrence M Blatt Journal: Mol Ther Nucleic Acids Date: 2021-12-11 Impact factor: 8.886