Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy
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
Affiliations
Motoi Kanagawa
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
Kazuhiro Kobayashi
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
Michiko Tajiri
Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan
Hiroshi Manya
Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan
Atsushi Kuga
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
Yoshiki Yamaguchi
Structural Glycobiology Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan
Keiko Akasaka-Manya
Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan
Jun-ichi Furukawa
Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo, Hokkaido 001-0021, Japan
Mamoru Mizuno
Laboratory of Glyco-organic Chemistry, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan
Hiroko Kawakami
Laboratory of Glyco-organic Chemistry, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan
Yasuro Shinohara
Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo, Hokkaido 001-0021, Japan
Yoshinao Wada
Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan
Tamao Endo
Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan
Tatsushi Toda
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
Glycosylation is an essential post-translational modification that underlies many biological processes and diseases. α-dystroglycan (α-DG) is a receptor for matrix and synaptic proteins that causes muscular dystrophy and lissencephaly upon its abnormal glycosylation (α-dystroglycanopathies). Here we identify the glycan unit ribitol 5-phosphate (Rbo5P), a phosphoric ester of pentose alcohol, in α-DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand-binding moiety. We show that enzyme activities of three major α-dystroglycanopathy-causing proteins are involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain-containing (ISPD) is cytidine diphosphate ribitol (CDP-Rbo) synthase. Fukutin and fukutin-related protein are sequentially acting Rbo5P transferases that use CDP-Rbo. Consequently, Rbo5P glycosylation is defective in α-dystroglycanopathy models. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation and provide insight into pathogenesis and therapeutic strategies in α-DG-associated diseases.
