Alternative splicing produces structural and functional changes in CUGBP2.
Alternative splicing produces structural and functional changes in CUGBP2.
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DOI：
10.1186/1471-2091-13-6
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发表时间：
2012-03-20
期刊：
影响因子：
--
通讯作者：
Tsukahara T
中科院分区：
文献类型：
--
作者：
Suzuki H;Takeuchi M;Sugiyama A;Alam AK;Vu LT;Sekiyama Y;Dam HC;Ohki SY;Tsukahara T
CELF/Bruno-like蛋白发挥多种作用，包括调控选择性剪接和翻译。这些RNA结合蛋白在n端含有两个RNA识别基序（RRM）结构域，在c端含有另一个RRM结构域。CUGBP2是该蛋白家族的成员，具有几个可选择剪接的外显子。本研究研究了外显子14的表达，这是一个选择性剪接的外显子，编码CUGBP2第三RRM的前半部分。在P19细胞诱导的神经细胞和大脑中，外显子14跳跃产物（R3δ）与其包合物的比例降低。尽管全长CUGBP2和CUGBP2 R3δ亚型对ACTN1基因平滑肌（SM）外显子的包含具有相似的作用，但这些亚型对胰岛素受体基因外显子11的跳跃具有相反的作用。此外，通过分子动力学模拟和核磁共振光谱分析对这些异构体的结构变化进行了检测，表明R3δ异构体的第三个RRM是柔性的，不形成RRM结构。我们的研究结果表明CUGBP2通过不同的机制调节ACTN1和胰岛素受体的剪接。CUGBP2外显子14的选择性剪接有助于胰岛素受体剪接的调节。目前的研究结果明确表明，导致CUGBP2三维结构变化的选择性剪接事件如何导致其生物活性的变化。
CELF/Bruno-like proteins play multiple roles, including the regulation of alternative splicing and translation. These RNA-binding proteins contain two RNA recognition motif (RRM) domains at the N-terminus and another RRM at the C-terminus. CUGBP2 is a member of this family of proteins that possesses several alternatively spliced exons. The present study investigated the expression of exon 14, which is an alternatively spliced exon and encodes the first half of the third RRM of CUGBP2. The ratio of exon 14 skipping product (R3δ) to its inclusion was reduced in neuronal cells induced from P19 cells and in the brain. Although full length CUGBP2 and the CUGBP2 R3δ isoforms showed a similar effect on the inclusion of the smooth muscle (SM) exon of the ACTN1 gene, these isoforms showed an opposite effect on the skipping of exon 11 in the insulin receptor gene. In addition, examination of structural changes in these isoforms by molecular dynamics simulation and NMR spectrometry suggested that the third RRM of R3δ isoform was flexible and did not form an RRM structure. Our results suggest that CUGBP2 regulates the splicing of ACTN1 and insulin receptor by different mechanisms. Alternative splicing of CUGBP2 exon 14 contributes to the regulation of the splicing of the insulin receptor. The present findings specifically show how alternative splicing events that result in three-dimensional structural changes in CUGBP2 can lead to changes in its biological activity.
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