LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy

Article

关键词: CONGENITAL MUSCULAR-DYSTROPHY;    ALPHA-DYSTROGLYCAN;    ABNORMAL GLYCOSYLATION;    LAMININ-BINDING;    DISRUPTION;    MUTATIONS;    EXPRESSION;    MEMBRANE;    COMPLEX;    CELLS;   

DOI  :  10.1038/nature12605

来源: SCIE

【 摘 要 】

The dense glycan coat that surrounds every cell is essential for cellular development and physiological function(1), and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-alpha 1,3-glucuronic acid-beta 1-](n) by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix(2,3). Reductions in the amount of [-3-xylose-alpha 1,3-glucuronic acid-beta 1-](n) (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy(4). However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype(5,6). This disparity can be attributed to our lack of knowledge of the cellular function of the LARGE-glycan repeat. Here we show that coordinated upregulation of Large and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking Large upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.

【 授权许可】

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