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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice.
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Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice.

机译：心肌肌钙蛋白T的化学和动力学性质的变化会导致转基因小鼠离散的心肌病。

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摘要

Cardiac troponin T (cTnT) is a central component of the regulatory thin filament. Mutations in cTnT have been linked to severe forms of familial hypertrophic cardiomyopathy. A mutational "hotspot" that leads to distinct clinical phenotypes has been identified at codon 92. Although the basic functional and structural roles of cTnT in modulating contractility are relatively well understood, the mechanisms that link point mutations in cTnT to the development of this complex cardiomyopathy are unknown. To address this question, we have taken a highly interdisciplinary approach by first determining the effects of the residue 92 mutations on the molecular flexibility and stability of cTnT by means of molecular dynamics simulations. To test whether the predicted alterations in thin filament structure could lead to distinct cardiomyopathies in vivo, we developed transgenic mouse models expressing either the Arg-92-Trp or Arg-92-Leu cTnT proteins in the heart. Characterization of these models at the cellular and whole-heart levels has revealed mutation-specific early alterations in transcriptional activation that result in distinct pathways of ventricular remodeling and contractile performance. Thus, our computational and experimental results show that changes in thin filament structure caused by single amino acid substitutions lead to differences in the biophysical properties of cTnT and alter disease pathogenesis.
机译：心肌肌钙蛋白T（cTnT）是调节性细丝的主要成分。 cTnT突变与严重的家族性肥厚型心肌病有关。密码子92处已鉴定出导致不同临床表型的突变“热点”。尽管相对了解cTnT在调节收缩性中的基本功能和结构作用，但将cTnT中点突变与这种复杂性心肌病的发展联系起来的机制未知。为了解决这个问题，我们采用了高度跨学科的方法，首先通过分子动力学模拟确定了残基92突变对cTnT分子柔性和稳定性的影响。为了测试预期的细丝结构改变是否会导致体内不同的心肌病，我们开发了在心脏中表达Arg-92-Trp或Arg-92-Leu cTnT蛋白的转基因小鼠模型。这些模型在细胞和全心脏水平上的表征揭示了转录激活中特定于突变的早期变化，这些变化导致心室重构和收缩性能的不同途径。因此，我们的计算和实验结果表明，由单个氨基酸取代引起的细丝结构变化导致cTnT的生物物理特性差异，并改变了疾病发病机理。

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