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

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Authors

LUKAVSKY Peter DAUJOTYTE Dalia TOLLERVEY James R ULE Jernej STUANI Cristiana BURATTI Emanuele BARALLE Francisco E DAMBERGER Fred F FRÉDÉRIC H-T Allain

Year of publication 2013
Type Article in Periodical
Magazine / Source NATURE STRUCTURAL & MOLECULAR BIOLOGY
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf
Doi http://dx.doi.org/10.1038/nsmb.2698
Field Genetics and molecular biology
Keywords TDP-43; RNA recognition; RRM; CFTR
Description 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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