The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition.
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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.
AuthorsPraissman, JL; Willer, T; Sheikh, MO; Toi, A; Chitayat, D; Lin, Y-Y; Lee, H; Stalnaker, SH; Wang, S; Prabhakar, PK; Nelson, SF; Stemple, DL; Moore, SA; Moremen, KW; Campbell, KP; Wells, L
- Genomic Medicine