Tyrosine phosphorylation as a regulator of dystrophin and beta-dystroglycan interaction: A molecular insight
Tyrosine phosphorylation as a regulator of dystrophin and beta-dystroglycan interaction: A molecular insight
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DOI：
10.1016/j.jmgm.2020.107623
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发表时间：
2020-09-01
影响因子：
2.9
通讯作者：
Naeem, Muhammad
中科院分区：
文献类型：
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作者：
Abdullah, Muhammad;Hassan, Adeena;Naeem, Muhammad
肌营养不良蛋白-β-肌营养不良蛋白聚糖相互作用由于其与肌营养不良症的发病机制相关，近年来获得了特别的关注。肌营养不良蛋白是肌营养不良蛋白相关蛋白复合物的重要组分，其除了膜稳定之外还在正常生理学和细胞信号传导中起作用，并为骨骼肌纤维提供完整性。已知肌营养不良蛋白的WW、EF-手和ZZ结构域与含有PPxY基序的β-肌营养不良蛋白聚糖（β-DG）的末端C末端区域结合，并且实验证明这种相互作用是由β-肌营养不良蛋白聚糖C末端的两个酪氨酸（Tyr（886）和Tyr（892））残基协调和调节的。这些酪氨酸残基以粘附依赖性方式磷酸化，破坏肌养蛋白-β-DG相互作用。肌营养不良蛋白与β-DG相互作用的失败导致肌营养不良症。在这项研究中，我们进行了分子对接分析的肌营养不良蛋白与磷酸化和突变的变体β-DG，以查明这种相互作用的实际性质在分子水平上。我们已经发现了由突变和酪氨酸磷酸化引起的β-DG分子的显著结构和构象变化，这些变化改变了其与肌营养不良蛋白相互作用的性质和位点。我们的研究结果不仅支持以前的研究结果，但也引起了注意以前未报道的发现，这种相互作用的性质和行为的不同β-DG变体与肌营养不良蛋白WW，EF-手和ZZ域。(C)2020爱思唯尔公司All rights reserved.
Dystrophin-beta-dystroglycan interaction has gained a special attention during current years due to its association with the pathogenesis of muscular dystrophies. Dystrophin is an important component of dystrophin associated protein complex that functions in the normal physiology and cell signaling in addition to membrane stabilization and provides integrity to skeletal muscle fibers. WW, EF-hand and ZZ domains of dystrophin are known to bind with extreme C-terminal region of beta-dystroglycan (beta-DG) containing PPxY motif and this interaction is experimentally proven to be coordinated and regulated by two tyrosine (Tyr(886) and Tyr(892)) residues in the C-terminus of beta-dystroglycan. These tyrosine residues are phosphorylated in adhesion dependent manner that disrupts dystrophin-beta-DG interaction. The failure of dystrophin to interact with beta-DG causes muscular dystrophies. In this study, we have performed molecular docking analysis of dystrophin with phosphorylated and mutated variants of beta-DG to pinpoint the actual nature of this interaction at molecular level. We have discovered significant structural and conformational changes in beta-DG molecule caused by mutations and tyrosine phosphorylation that alter the nature and site of its interaction with dystrophin. Our results not only support the previous findings but also bring to attention previously unreported discoveries about the nature of this interaction and behavior of different beta-DG variants with dystrophin WW, EF-hand and ZZ domains. (C) 2020 Elsevier Inc. All rights reserved.