Calcium-induced structural transition in the regulatory domain of human cardiac troponin C
Calcium-induced structural transition in the regulatory domain of human cardiac troponin C
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DOI：
10.1021/bi971223d
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发表时间：
1997-10-07
期刊：
影响因子：
2.9
通讯作者：
Sykes, BD
中科院分区：
文献类型：
--
作者：
Spyracopoulos, L;Li, MX;Sykes, BD
虽然钙与肌钙蛋白C （TnC）结合会触发骨骼肌和心肌的收缩，但有明确的证据表明可能涉及不同的机制。例如，心肌肌丝的激活发生在与TnC上的单个调节位点结合时，而快速骨骼肌丝的激活发生在与两个调节位点结合时。由于缺乏心肌TnC对钙反应的结构细节，在分子水平上尚不了解心肌和骨骼肌纤维活化之间的生理差异。我们利用多核、多维核磁共振波谱技术确定了人类心脏TnC载脂蛋白和钙饱和调节结构域的溶液结构。载脂蛋白人类心脏TnC的结构与载脂蛋白火鸡骨骼TnC的结构非常相似，尽管在i位点存在关键的氨基酸取代。与骨骼蛋白的情况相反，钙诱导的心脏调节结构域的构象转变不涉及调节结构域的“开放”，以及随之而来的大量疏水表面积的暴露。这一结果对于心肌TnC与心肌肌钙蛋白I相互作用的潜在独特方面以及钙致敏药物对心肌肌丝调节的修饰具有重要意义。
While calcium binding to troponin C (TnC) triggers the contraction of both skeletal and cardiac muscle, there is clear evidence that different mechanisms may be involved. For example, activation of heart myofilaments occurs with binding to a single regulatory site on TnC, whereas activation of fast skeletal myofilaments occurs with binding to two regulatory sites. The physiological difference between activation of cardiac and skeletal myofilaments is not understood at the molecular level due to a lack of structural details for the response of cardiac TnC to calcium. We determined the solution structures of the apo and calcium-saturated regulatory domain of human cardiac TnC by using multinuclear, multidimensional nuclear magnetic resonance spectroscopy. The structure of apo human cardiac TnC is very similar to that of apo turkey skeletal TnC even though there are critical amino acid substitutions in site I. In contrast to the case with the skeletal protein, the calcium-induced conformational transition in the cardiac regulatory domain does not involve an ''opening'' of the regulatory domain, and the concomitant exposure of a substantial hydrophobic surface area. This result has important implications with regard to potential unique aspects of the interaction of cardiac TnC with cardiac troponin I and of modification of cardiac myofilament regulation by calcium-sensitizer drugs.