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

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          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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          Author and article information

          Journal
          Cell Reports
          Cell Reports
          Elsevier BV
          22111247
          March 2016
          March 2016
          : 14
          : 9
          : 2209-2223
          Article
          10.1016/j.celrep.2016.02.017
          26923585
          2fb6074e-db00-45a4-a9b0-8cd6459899d7
          © 2016

          https://www.elsevier.com/tdm/userlicense/1.0/

          http://creativecommons.org/licenses/by-nc-nd/4.0/

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