Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43

Abstract

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.

DOI: 10.1038/nsmb.2698
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@article{Lukavsky2013MolecularBO, title={Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43}, author={Peter J. Lukavsky and Dalia Daujotytė and James R. Tollervey and Jernej Ule and Cristiana Stuani and Emanuele Buratti and Francisco E. Baralle and Fred Franz Damberger and Fr{\'e}d{\'e}ric Hai-Trieu Allain}, journal={Nature Structural &Molecular Biology}, year={2013}, volume={20}, pages={1443-1449} }