LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy.
LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy.
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围绕着每个细胞的致密的葡聚糖衣对于细胞的发育和生理功能是必不可少的，人们越来越认识到它的组成是高度动态的。多糖重复单元[-3-木糖-α1，3-葡萄糖醛酸-β1-]n翻译后被类乙酰氨基葡萄糖转移酶(LIGH)加成，糖蛋白营养不良聚糖作为细胞外基质中蛋白质的受体发挥作用。营养不良患者体内的[-3-木糖-α1，3-葡糖醛酸-β1-]n(以下简称大聚糖)含量减少会导致不同形式的肌营养不良。然而，无论是病人还是小鼠的研究都没有发现糖基化状态和表型之间的明显相关性。这种差异可以归因于我们对大-糖链重复序列的细胞功能缺乏了解。在这里，我们表明，在分化的小鼠肌肉中，大的和营养不良的葡聚糖的协同上调促进了大的葡聚糖重复链的快速延伸。利用人工合成的大糖链重复序列，我们证明了大糖链的延伸与其与细胞外基质配体的结合能力之间存在着直接的相关性。阻止肌肉再生过程中的大量上调会导致营养不良多糖的合成，伴随着基底膜不致密、不成熟的神经肌肉连接和易于营养不良的肌肉功能障碍。这与疾病临床严重程度越高的患者大糖链重复数越少的发现是一致的。我们的结果显示，营养不良多糖的大小是一种可调节的细胞外基质蛋白支架，其延伸是正常骨骼肌功能所必需的。
The dense glycan coat that surrounds every cell is essential for cellular development and physiological function, and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-α1,3-glucuronic acid-β1-]n by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix. Reductions in the amount of [-3-xylose-α1,3-glucuronic acid-β1-]n (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy. However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype. 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.
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