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.
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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 |
Journal | Cell reports
(Cell Rep)
Vol. 14
Issue 9
Pg. 2209-2223
(Mar 08 2016)
ISSN: 2211-1247 [Electronic] United States |
PMID | 26923585
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- FKTN protein, human
- Membrane Proteins
- Pentosephosphates
- Proteins
- ribitol-5-phosphate
- FKRP protein, human
- Pentosyltransferases
- Nucleotidyltransferases
- CRPPA protein, human
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Topics |
- Amino Acid Sequence
- Carbohydrate Conformation
- Carbohydrate Sequence
- Glycosylation
- HEK293 Cells
- Humans
- Membrane Proteins
(physiology)
- Muscular Dystrophies
(enzymology, genetics)
- Mutation
- Nucleotidyltransferases
(genetics)
- Pentosephosphates
(metabolism)
- Pentosyltransferases
- Protein Processing, Post-Translational
- Proteins
(physiology)
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