Alternative splicing produces structural and functional changes in CUGBP2
- Equal contributors
1 Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, Ishikawa 923-1292, Japan
2 School of Materials Science, Japan Advanced Institute of Science and Technology, Ishikawa 923-1292, Japan
3 School of Knowledge Science, Japan Advanced Institute of Science and Technology, Ishikawa 923-1292, Japan
4 Japan Science and Technology Agency, ERATO, Shimoda Nano-Liquid Process Project, 2-5-3 Asahidai, Nomi, Ishikawa 923-1211, Japan
5 Department of Pharmacy, University of Rajshahi, Rajshahi 6205, Bangladesh
BMC Biochemistry 2012, 13:6 doi:10.1186/1471-2091-13-6Published: 20 March 2012
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.