TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail

作者：Emanuele Buratti, Antonia Brindisi, Maurizio Giombi, Sergio Gabriel Tisminetzky, Youhna M. Ayala, Francisco Ernesto Baralle · 发表于：Journal of Biological Chemistry · 年份：2005 · DOI：10.1074/jbc.m505557200 · 被引用次数：463 · 研究领域：RNA Research and Splicing、Neurogenetic and Muscular Disorders Research、RNA and protein synthesis mechanisms

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, hnRNP A2/B1 and hnRNP A1. 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.