Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C
Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C
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DOI：
10.1371/journal.pone.0059206
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发表时间：
2013-03-19
期刊：
影响因子：
3.7
通讯作者：
Yacoub, Magdi H.
中科院分区：
文献类型：
--
作者：
Gajendrarao, Poornima;Krishnamoorthy, Navaneethakrishnan;Yacoub, Magdi H.
心肌肌球蛋白结合蛋白-C（cMyBP-C）是一种多结构域（C 0-C10）蛋白，通过与肌球蛋白、肌动蛋白和其他肌节蛋白相互作用来调节心肌收缩。这种蛋白质的几种突变导致家族性肥厚型心肌病（HCM）。cMyBP-C的结构域C1在蛋白质与肌动蛋白和肌球蛋白的相互作用中起着核心作用。本文利用计算生物学技术，结合其晶体结构，研究了C1结构域Arg 177 His、Ala 216 Thr和Glu 258 Lys三个致病突变的结构-功能关系。结果表明，每个突变可以影响结构域C1的结构特性，因此它的结构完整性，通过改变分子内的安排在一个独特的模式。这些突变还改变了表面电荷分布，这可能会影响C1与其他肌节蛋白的结合，从而影响收缩功能。C1突变体的这些结构后果对于理解该疾病的分子机制可能是有价值的。
Cardiac myosin binding protein-C (cMyBP-C) is a multi-domain (C0-C10) protein that regulates heart muscle contraction through interaction with myosin, actin and other sarcomeric proteins. Several mutations of this protein cause familial hypertrophic cardiomyopathy (HCM). Domain C1 of cMyBP-C plays a central role in protein interactions with actin and myosin. Here, we studied structure-function relationship of three disease causing mutations, Arg177His, Ala216Thr and Glu258Lys of the domain C1 using computational biology techniques with its available X-ray crystal structure. The results suggest that each mutation could affect structural properties of the domain C1, and hence it's structural integrity through modifying intra-molecular arrangements in a distinct mode. The mutations also change surface charge distributions, which could impact the binding of C1 with other sarcomeric proteins thereby affecting contractile function. These structural consequences of the C1 mutants could be valuable to understand the molecular mechanisms for the disease.