Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy

• DOI: 10.1016/j.celrep.2016.02.017
• Publication Date: 2016-02-25T16:58:38Z
• Authors: Motoi Kanagawa; Kazuhiro Kobayashi; Michiko Tajiri; Hiroshi Manya; Atsushi Kuga; Yoshiki Yamaguchi; Keiko Akasaka-Manya; Jun-ichi Furukawa; Mamoru Mizuno; Hiroko Kawakami; Yasuro Shinohara; Yoshinao Wada; Tamao Endo; Tatsushi Toda
• Keywords: Ribitol

Glycosylation is an essential post-translational modification that underlies many biological processes and diseases. α-dystroglycan (α-DG) a receptor for matrix synaptic proteins causes muscular dystrophy lissencephaly upon its abnormal glycosylation (α-dystroglycanopathies). Here we identify the glycan unit ribitol 5-phosphate (Rbo5P), phosphoric ester of pentose alcohol, in α-DG. Rbo5P forms tandem repeat functions as scaffold formation ligand-binding moiety. We show enzyme activities three major α-dystroglycanopathy-causing are involved synthesis Rbo5P. Isoprenoid synthase domain-containing (ISPD) cytidine diphosphate (CDP-Rbo) synthase. Fukutin fukutin-related protein sequentially acting transferases use CDP-Rbo. Consequently, defective α-dystroglycanopathy models. Supplementation CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish molecular basis mammalian provide insight into pathogenesis therapeutic strategies α-DG-associated