Bin1 Src Homology 3 Domain Acts as a Scaffold for Myofiber Sarcomere Assembly
Bin1 Src Homology 3 Domain Acts as a Scaffold for Myofiber Sarcomere Assembly
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DOI：
10.1074/jbc.m109.029538
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发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Megeney, Lynn A.
中科院分区：
文献类型：
--
作者：
Fernando, Pasan;Sandoz, Jacqueline S.;Megeney, Lynn A.
在骨骼肌发育中，控制肌细胞特化的基因和调节因子被很好地描述。尽管有这些知识，但调节肌纤维蛋白协调组装成功能性收缩单位或肌节的机制仍不明确。在这里，我们探讨了模块化结构域蛋白，如Bin 1协调蛋白质相互作用，以促进肌节形成的假设。我们证明，Bin 1促进肌节组织通过蛋白质-蛋白质相互作用介导的Src同源3（SH 3）结构域。我们在表达Bin 1 SH 3区域的小鼠模型中观察到肌纤维大小和结构组织的严重紊乱。此外，尽管骨骼肌特异性蛋白的积累，卫星细胞衍生的肌发生是有限的。我们的实验表明，Bin 1 SH 3结构域与肌动蛋白和肌球蛋白丝以及前肌生成激酶Cdk 5形成瞬时蛋白复合物。Bin 1还与肌联蛋白的Cdk 5磷酸化结构域相关。总的来说，这些观察结果表明，Bin 1显示蛋白质支架样的特性，并与指导肌节蛋白组装和肌纤维成熟的重要肌节因子结合。
In skeletal muscle development, the genes and regulatory factors that govern the specification of myocytes are well described. Despite this knowledge, the mechanisms that regulate the coordinated assembly of myofiber proteins into the functional contractile unit or sarcomere remain undefined. Here we explored the hypothesis that modular domain proteins such as Bin1 coordinate protein interactions to promote sarcomere formation. We demonstrate that Bin1 facilitates sarcomere organization through protein-protein interactions as mediated by the Src homology 3 (SH3) domain. We observed a profound disorder in myofiber size and structural organization in a murine model expressing the Bin1 SH3 region. In addition, satellite cell-derived myogenesis was limited despite the accumulation of skeletal muscle-specific proteins. Our experiments revealed that the Bin1 SH3 domain formed transient protein complexes with both actin and myosin filaments and the pro-myogenic kinase Cdk5. Bin1 also associated with a Cdk5 phosphorylation domain of titin. Collectively, these observations suggest that Bin1 displays protein scaffold-like properties and binds with sarcomeric factors important in directing sarcomere protein assembly and myofiber maturation.