Molecular recognition by LARGE is essential for expression of functional dystroglycan
Molecular recognition by LARGE is essential for expression of functional dystroglycan
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DOI：
10.1016/j.cell.2004.06.003
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发表时间：
2004-06-25
期刊：
影响因子：
64.5
通讯作者：
Campbell, KP
中科院分区：
文献类型：
--
作者：
Kanagawa, M;Saito, F;Campbell, KP
在越来越多的肌营养不良症中，α-肌营养不良多糖的配体结合活性降低与肌肉和中枢神经系统的发病有关。人们普遍认为，α-肌营养不良聚糖的翻译后加工对功能性肌营养不良聚糖的表达至关重要。在这里，我们发现α-肌营养不良多糖的N-末端结构域和部分粘蛋白样结构域对于高亲和力的层粘连蛋白受体的功能是必不可少的。糖基转移酶对α-肌营养不良聚糖的翻译后修饰发生在粘蛋白样域，但N-末端结构域与大糖链相互作用，定义了启动功能性糖基化所必需的细胞内酶-底物识别基序。肌营养不良蛋白聚糖缺陷肌肉中的基因替换表明，肌营养不良蛋白多糖的C-末端结构域仅足以组装肌营养不良蛋白-糖蛋白复合体，但要防止肌肉退化，需要通过大量识别和糖基化来表达功能性肌营养不良蛋白聚糖。因此，对肌营养不良多糖的分子识别是生物合成途径中产生成熟和功能性肌营养不良多糖的关键决定因素。
Reduced ligand binding activity of alpha-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies. Posttranslational processing of alpha-dystroglycan is generally accepted to be critical for the expression of functional dystroglycan. Here we show that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan are essential for high-affinity laminin-receptor function. Posttranslational modification of alpha-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required. Therefore, molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan.