Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice
Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice
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DOI：
10.1073/pnas.0509181102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Tardiff, JC
中科院分区：
文献类型：
--
作者：
Ertz-Berger, BR;He, HM;Tardiff, JC
心肌肌钙蛋白 T (cTnT) 是调节性细丝的核心成分。 cTnT 突变与严重的家族性肥厚型心肌病有关。已在密码子 92 处鉴定出导致不同临床表型的突变“热点”。尽管 cTnT 在调节收缩力中的基本功能和结构作用已相对较好地了解，但将 cTnT 点突变与这种复杂心肌病的发展联系起来的机制尚不清楚。为了解决这个问题，我们采取了高度跨学科的方法，首先通过分子动力学模拟确定残基 92 突变对 cTnT 分子灵活性和稳定性的影响。为了测试细丝结构的预测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突变特异性的早期改变，导致心室重塑和收缩性能的不同途径。因此，我们的计算和实验结果表明，单个氨基酸取代引起的细丝结构变化会导致 cTnT 生物物理特性的差异并改变疾病发病机制。
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.