Details

Autor(en) / Beteiligte

• Lukavsky, Peter J
• Daujotyte, Dalia
• Tollervey, James R
• Ule, Jernej
• Stuani, Cristiana
• Buratti, Emanuele
• Baralle, Francisco E
• Damberger, Fred F
• Allain, Frédéric H-T

Titel

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

Ist Teil von

• Nature structural & molecular biology, 2013-12, Vol.20 (12), p.1443-1449

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.