Investigation of zone for dystroglycan glycosylation

Research abstract

Glycosylation is an essential post-translational modification in living organism and thus its defects are often associated with human diseases. Dystroglycan is a transmembrane protein complex that links extracellular matrix and cytoskeletons. Glycosylation is required for the ligand binding activity of dystroglycan and abnormal glycosylation causes muscular dystrophy and brain anomaly. Details in sugar chain structure of dystroglycan had been unknown for a long time, but recently we revealed that the sugar chain contains ribitol-phosphate, a novel modification unit in mammals, and also identified gene functions that are involved in the biosynthesis of this novel modification. In addition, sugar chain of dystroglycan contains a repeating unit consisting of glucuronic acid (GlcA) and xylose (Xyl), which serves the ligand binding domain. More than ten different transferases are involved in the modification of ribitol phosphate and GlcA/Xyl repeats. A question is what mechanism supports for such specific modifications correctly taken place on dystroglycan. We believe that researches on organelle zone would give an answer. In this project, we will try to identify the zone for dystroglycan glycosylation and mechanism for zone’s formation and action.

Original papers

1. Kanagawa, M., Kobayashi, K., Tajiri, M., Manya, H., Kuga, A., Yamaguchi, Y., Akasaka-Manya, K., Furukawa, J., Mizuno, M., Kawakami, H., Shinohara, Y., Wada, Y., Endo, T., and Toda, T. (2016) Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy. Cell Rep. 14, 2209-2223
2. Kanagawa, M., Yu, CC., Ito, C., Fukada, SI., Hozoji-Inada, M., Chiyo, T., Kuga, A., Matsuo, M., Sato, K., Yamaguchi, M., Ito, T., Ohtsuka, Y., Katanosaka, Y., Miyagoe-Suzuki, Y., Naruse, K., Kobayashi, K., Okada, T., Takeda, S., and Toda, T. (2013)　Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression.　Hum. Mol. Genet. 22, 3003-3015
3. Taniguchi-Ikeda, M., Kobayashi, K., Kanagawa, M., Yu, C-C., Mori, K., Oda, T., Kuga, A., Kurahashi, H., Akman, H.O., DiMauro, S., Kaji, R., Yokota, T., Takeda, S.I., and Toda, T. (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature 478, 127-131
4. Hara, Y., Kanagawa, M. (co-first), Kunz, S., Yoshida-Moriguchi,T., Satz, J.S., Kobayashi, Y.M., Zhu, Z., Burden, S.J., Oldstone, M.B.A., and Campbell, K.P. (2011) LARGE-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection. Proc. Natl. Acad. Sci. USA. 108, 17426-17431
5. Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y.M., Muschler, J., Dumanski, J.P., Michele, D.E., Oldstone, M.B., and Campbell. K.P. (2004) Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell 117, 953-964

Reviews

1. Kanagawa, M., Toda, T. (2018) Ribitol-phosphate-a newly identified posttranslational glycosylation unit in mammals: structure, modification enzymes, and relationship to human diseases. J. Biochem. 163, 359-369
2. Kanagawa, M., Toda, T. (2017) Muscular dystrophy with ribitol-phosphate deficiency: a novel post-translational mechanism in dystroglycanopathy. J. Neuromuscul. Dis. 4, 259-267
3. Kanagawa, M. (2014) Dystroglycan glycosylation and its involvement in muscular dystrophy. Trends Glycosci. Glycotech. 26, 41-57
4. Kanagawa, M., and Toda T. (2006) The genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in the pathogenesis. J. Hum. Genet. 51, 915-926