Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
089701
Wellcome Trust - United Kingdom
MC_U105185858
Medical Research Council - United Kingdom
PubMed
24240615
DOI
10.1038/nsmb.2698
PII: nsmb.2698
Knihovny.cz E-resources
- MeSH
- DNA-Binding Proteins chemistry metabolism physiology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Sequence Data MeSH
- Nuclear Magnetic Resonance, Biomolecular MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics metabolism MeSH
- RNA-Binding Proteins chemistry metabolism physiology MeSH
- Amino Acid Sequence MeSH
- RNA Splicing physiology MeSH
- Protein Structure, Tertiary MeSH
- Binding Sites MeSH
- Base Composition MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CFTR protein, human MeSH Browser
- DNA-Binding Proteins MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator MeSH
- RNA-Binding Proteins MeSH
TDP-43 encodes an alternative-splicing regulator with tandem RNA-recognition motifs (RRMs). The protein regulates cystic fibrosis transmembrane regulator (CFTR) exon 9 splicing through binding to long UG-rich RNA sequences and is found in cytoplasmic inclusions of several neurodegenerative diseases. We solved the solution structure of the TDP-43 RRMs in complex with UG-rich RNA. Ten nucleotides are bound by both RRMs, and six are recognized sequence specifically. Among these, a central G interacts with both RRMs and stabilizes a new tandem RRM arrangement. Mutations that eliminate recognition of this key nucleotide or crucial inter-RRM interactions disrupt RNA binding and TDP-43-dependent splicing regulation. In contrast, point mutations that affect base-specific recognition in either RRM have weaker effects. Our findings reveal not only how TDP-43 recognizes UG repeats but also how RNA binding-dependent inter-RRM interactions are crucial for TDP-43 function.
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PDB
4BS2
