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Nat Struct Mol Biol. 2013 Dec;20(12):1443-9. doi: 10.1038/nsmb.2698. Epub 2013 Nov 17.

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

Author information

1
1] Central European Institute of Technology, Masaryk University, Brno, Czech Republic. [2] Institute of Molecular Biology and Biophysics, Eidgenössische Technische Hochschule Hönggerberg, Zürich, Switzerland.

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.

PMID:
24240615
DOI:
10.1038/nsmb.2698
[Indexed for MEDLINE]

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