TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail - An important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing
TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail - An important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing
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DOI：
10.1074/jbc.m505557200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Baralle, FE
中科院分区：
文献类型：
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作者：
Buratti, E;Brindisi, A;Baralle, FE
TDP-43是一种功能未知的高度保守的核因子，可与ug重复序列结合，参与囊性纤维化跨膜电导调节因子外显子9的剪接抑制。我们分析了TDP-43与其他剪接因子的相互作用，并确定了决定这一生物学功能的蛋白质/蛋白质识别事件的关键区域。我们在这里证明了TDP-43的C-末端区域能够直接与多相核核糖核蛋白(HnRNP)家族的几种蛋白质结合，特别是hnRNPA2/B1和hnRNPA1。突变分析表明，缺失C-末端的TDP-43蛋白不能抑制剪接，可能是因为它们不能形成富含hnRNP的复合体参与剪接抑制。最后，通过剪接复合体分析，我们发现TDP-43介导的剪接抑制发生在剪接体组装的早期阶段。
TDP-43 is a highly conserved nuclear factor of yet unknown function that binds to ug-repeated sequences and is responsible for cystic fibrosis transmembrane conductance regulator exon 9 splicing inhibition. We have analyzed TDP-43 interactions with other splicing factors and identified the critical regions for the protein/protein recognition events that determine this biological function. We show here that the C-terminal region of TDP-43 is capable of binding directly to several proteins of the heterogeneous nuclear ribonucleoprotein ( hnRNP) family with well known splicing inhibitory activity, in particular, hnRNPA2/ B1 and hnRNPA1. Mutational analysis showed that TDP-43 proteins lacking the C-terminal region could not inhibit splicing probably because they were unable to form the hnRNP-rich complex involved in splicing inhibition. Finally, through splicing complex analysis, we show that splicing inhibition mediated by TDP-43 occurs at the earliest stages of spliceosomal assembly.