title: Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy.
abstract: 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.
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Tajiri
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuga
authors.affiliation: 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.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akasaka-Manya
authors.affiliation: 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.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Furukawa
authors.affiliation: Laboratory of Glyco-organic Chemistry, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Laboratory of Glyco-organic Chemistry, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: 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.
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Shinohara
authors.affiliation: Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan. Electronic address: waday@lab.mch.pref.osaka.jp.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan. Electronic address: endo@tmig.or.jp.
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan. Electronic address: toda@med.kobe-u.ac.jp.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000595:Amino Acid Sequence; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009136:Muscular Dystrophies / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics; D010428:Pentosephosphates / Q000378:metabolism*; D010430:Pentosyltransferases; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000502:physiology*
chemical_list: C113587:FKTN protein, human; D008565:Membrane Proteins; D010428:Pentosephosphates; D011506:Proteins; C041025:ribitol-5-phosphate; C443107:FKRP protein, human; D010430:Pentosyltransferases; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human