Mutations in the β-myosin rod cause myosin storage myopathy via multiple mechanisms
Mutations in the β-myosin rod cause myosin storage myopathy via multiple mechanisms
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DOI：
10.1073/pnas.0900107106
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发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Leinwand, Leslie A.
中科院分区：
文献类型：
--
作者：
Armel, Thomas Z.;Leinwand, Leslie A.
肌球蛋白沉积性肌病（MSM）是一种先天性肌病，其特征在于在大多数I型肌纤维中存在肌球蛋白的肌膜下包涵体，并且已经与慢肌/心肌肌球蛋白β-MyHC（MYH 7）中的4种突变相关。虽然MYH 7中> 230种致病突变中的大多数位于分子的球状头部区域，但导致MSM的突变是位于α-螺旋卷曲螺旋尾部的MYH 7突变子集的一部分。肌球蛋白头部的突变被认为会影响该分子的ATP酶和肌动蛋白结合特性。然而，到目前为止，还没有报道的发病机制的突变在杆区的肌球蛋白的分子。在这里，我们提出了4个突变负责MSM：L1793 P，R1845 W，E1886 K和H1901 L的分析。我们发现，每一个MSM突变有不同的分子表型，这表明有多种机制，MSM可以引起。这些机制的范围从单个蛋白质（L1793 P）的热力学和功能不规则性，到由蛋白质（R1845 W，E1886 K和H1901 L）形成的细丝的组装和稳定性的不同缺陷。除了进一步加深我们对MSM的理解外，这些观察结果还首次深入了解了突变如何影响肌球蛋白的杆状区域，并为未来研究该分子区域的致病突变提供了框架。
Myosin storage myopathy (MSM) is a congenital myopathy characterized by the presence of subsarcolemmal inclusions of myosin in the majority of type I muscle fibers, and has been linked to 4 mutations in the slow/cardiac muscle myosin, beta-MyHC (MYH7). Although the majority of the > 230 disease causing mutations in MYH7 are located in the globular head region of the molecule, those responsible for MSM are part of a subset of MYH7 mutations that are located in the alpha-helical coiled-coil tail. Mutations in the myosin head are thought to affect the ATPase and actin-binding properties of the molecule. To date, however, there are no reports of the molecular mechanism of pathogenesis for mutations in the rod region of muscle myosins. Here, we present analysis of 4 mutations responsible for MSM: L1793P, R1845W, E1886K, and H1901L. We show that each MSM mutation has a different molecular phenotype, suggesting that there are multiple mechanisms by which MSM can be caused. These mechanisms range from thermodynamic and functional irregularities of individual proteins (L1793P), to varying defects in the assembly and stability of filaments formed from the proteins ( R1845W, E1886K, and H1901L). In addition to furthering our understanding of MSM, these observations provide the first insight into how mutations affect the rod region of muscle myosins, and provide a framework for future studies of disease-causing mutations in this region of the molecule.