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Cell Rep. 2016 Mar 8;14(9):2209-2223. doi: 10.1016/j.celrep.2016.02.017. Epub 2016 Feb 25.

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

Author information

1
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
2
Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
3
Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
4
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.
5
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.
6
Laboratory of Glyco-organic Chemistry, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan.
7
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.
8
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.
9
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.

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.

PMID:
26923585
DOI:
10.1016/j.celrep.2016.02.017
[Indexed for MEDLINE]
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