Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~ 90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

中文翻译：

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POMK 通过大介导的基质聚糖延伸调节肌营养不良聚糖功能


基质聚糖 [-GlcA-β1,3-Xyl-α1,3-]n 在许多组织中充当含有层粘连蛋白-G 结构域（包括层粘连蛋白、聚集蛋白和基底膜聚糖）的细胞外基质蛋白的支架。在骨骼肌分化和再生过程中，LARGE-Glucosaminyltransferase 1 (LARGE1) 在 α-dystroglycan (α-DG) 上合成基质聚糖并延伸；然而，调节基质聚糖伸长的机制尚不清楚。在这里，我们表明蛋白 O-甘露糖激酶 (POMK) 在基质聚糖合成之前磷酸化核心 M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) 的甘露糖，是 LARGE1 介导的全长生成所必需的α-DG (~150 kDa) 上的基质聚糖。在小鼠骨骼肌中缺乏 Pomk 基因表达的情况下，LARGE1 合成一种非常短的基质聚糖，产生约 90 kDa 的 α-DG，它与层粘连蛋白结合，但不能防止偏心收缩引起的力量损失或肌肉病理。溶液核磁共振波谱研究表明，LARGE1 直接与核心 M3 相互作用，并优先与磷酸化形式结合。总的来说，我们的研究表明，POMK 对核心 M3 的磷酸化使 LARGE1 能够延长 α-DG 上的基质聚糖，从而预防肌营养不良症。