Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7
- Institute of Molecular Biology and Biophysics, ETH Zurich, Switzerland
Abstract
HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function. The disruption of the inter-RRM interaction or the loss of RNA binding capacity of either RRM impairs splicing repression by hnRNP A1. Furthermore, both binding sites within the ISS-N1 are important for splicing repression and their contributions are cumulative rather than synergistic.
Article and author information
Author details
Frédéric Hai-Trieu Allain
Funding
ETH Zurich
- Frédéric Hai-Trieu Allain
Centre National de la Recherche Scientifique
- Pierre Barraud
Swiss National Science Foundation NCCR Structural Biology
- Frédéric Hai-Trieu Allain
Swiss National Science Foundation NCCR RNA and Disease
- Frédéric Hai-Trieu Allain
SMA Europe
- Frédéric Hai-Trieu Allain
ETH Fellowship Program (Post-doc fellowship)
- Pierre Barraud
Novartis Foundation (Post-doc fellowship)
- Pierre Barraud
Cure SMA
- Antoine Cléry
- Frédéric Hai-Trieu Allain
Fondation Suisse de Recherche sur les Maladies Musculaires
- Antoine Cléry
- Frédéric Hai-Trieu Allain
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Beusch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7
eLife 6:e25736.
https://doi.org/10.7554/eLife.25736
