PUBLICATION
The functional O-mannose glycan on ?-dystroglycan contains a phospho-ribitol primed for matriglycan addition
- Authors
- Praissman, J.L., Willer, T., Sheikh, M.O., Toi, A., Chitayat, D., Lin, Y.Y., Lee, H., Stalnaker, S.H., Wang, S., Prabhakar, P.K., Nelson, S.F., Stemple, D.L., Moore, S.A., Moremen, K.W., Campbell, K.P., Wells, L.
- ID
- ZDB-PUB-160501-5
- Date
- 2016
- Source
- eLIFE 5: (Journal)
- Registered Authors
- Lin, Yung-Yao, Stemple, Derek L.
- Keywords
- biochemistry, human, human biology, medicine, zebrafish
- MeSH Terms
-
- Ribitol/analysis
- Mannose/analysis
- Nucleotidyltransferases/metabolism
- Polysaccharides/analysis*
- Dystroglycans/chemistry*
- PubMed
- 27130732 Full text @ Elife
Abstract
Multiple glycosyltransferases are essential for the proper modification of alpha-dystroglycan, as mutations in the encoding genes cause congenital/limb-girdle muscular dystrophies. Here we elucidate further the structure of an O-mannose-initiated glycan on alpha-dystroglycan that is required to generate its extracellular matrix-binding polysaccharide. This functional glycan contains a novel ribitol structure that links a phosphotrisaccharide to xylose. ISPD is a CDP-ribitol (ribose) pyrophosphorylase that generates the reduced sugar nucleotide for the insertion of ribitol in a phosphodiester linkage to the glycoprotein. TMEM5 is a UDP-xylosyl transferase that elaborates the structure. We demonstrate in a zebrafish model as well as in a human patient that defects in TMEM5 result in muscular dystrophy in combination with abnormal brain development. Thus, we propose a novel structure - a ribitol in a phosphodiester linkage - for the moiety on which TMEM5, B4GAT1, and LARGE act to generate the functional receptor for ECM proteins having LG domains.
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Phenotype
Mutations / Transgenics
Human Disease / Model
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