Informace o publikaci

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

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

Rok publikování 2013
Druh Článek v odborném periodiku
Časopis / Zdroj NATURE STRUCTURAL & MOLECULAR BIOLOGY
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www http://www.nature.com/nsmb/journal/v20/n12/pdf/nsmb.2698.pdf
Doi http://dx.doi.org/10.1038/nsmb.2698
Obor Genetika a molekulární biologie
Klíčová slova TDP-43; RNA recognition; RRM; CFTR
Popis 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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