An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy
An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy
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DOI：
10.1007/s12265-015-9624-6
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发表时间：
2015-06-01
影响因子：
3.4
通讯作者：
Yacoub, Magdi
中科院分区：
文献类型：
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作者：
Gajendrarao, Poornima;Krishnamoorthy, Navaneethakrishnan;Yacoub, Magdi
编码心肌肌球蛋白结合蛋白-C (cMyBP-C)（一种多结构域 (C0-C10) 蛋白）的基因突变是遗传性肥厚型心肌病的主要致病因素。携带该基因突变的患者具有极其异质的临床病程，其中一些进展为终末期心力衰竭。这种变化的原因尚不清楚。我们在此描述了患有严重 HCM 表型的患者的 C1 (E258K) 和 C2 (E441K) 结构域双突变的分子模型。通过引入双突变和单突变构建了 C1-基序-C2 复合物的三维结构。在生理条件下进行10 ns 的分子动力学模拟。结果表明，单独的 E258K 和 E441K 都可以通过构象变化主要影响天然结构域以及附近的基序，并在它们共存时产生相加效应。这些变化涉及基序的重要区域，例如磷酸化和潜在的肌动蛋白结合位点。此外，电荷反转突变改变了复合物的表面静电特性。此外，我们研究了蛋白质表达，结果表明突变蛋白得到了表达，我们可以假设严重的表型不是由于单倍体不足造成的。然而，需要对人类基因表达进行更多研究来证实这一假设。影响 cMyBP-C 调节性 N 末端的双突变有可能协同干扰与邻近结构域和其他肌节蛋白的结合。这些影响可能解释了在复杂的 cMyBP-C 基因型中观察到的严重表型和临床过程。
Mutations in the gene coding for cardiac myosin binding protein-C (cMyBP-C), a multi-domain (C0-C10) protein, are a major causative factor for inherited hypertrophic cardiomyopathy. Patients carrying mutations in this gene have an extremely heterogeneous clinical course, with some progressing to end-stage heart failure. The cause of this variability is unknown. We here describe molecular modeling of a double mutation in domains C1 (E258K) and C2 (E441K) in a patient with severe HCM phenotype. The three-dimensional structure for the C1-motif-C2 complex was constructed with double and single mutations being introduced. Molecular dynamic simulations were performed for 10 ns under physiological conditions. The results showed that both E258K and E441K in isolation can predominantly affect the native domain as well as the nearby motif via conformational changes and result in an additive effect when they coexist. These changes involve important regions of the motif such as phosphorylation and potential actin-binding sites. Moreover, the charge reversal mutations altered the surface electrostatic properties of the complex. In addition, we studied protein expression, which showed that the mutant proteins were expressed and we can suppose that the severe phenotype was not due to haploinsufficiency. However, additional studies on human gene expression will need to confirm this hypothesis. The double mutation affecting the regulatory N-terminal of cMyBP-C have the potential of synergistically interfering with the binding to neighbouring domains and other sarcomeric proteins. These effects may account for the severe phenotype and clinical course observed in the complex cMyBP-C genotypes.