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首页> 外文期刊>Biochemistry >Troponin T core structure and the regulatory NH2-terminal variable region.
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Troponin T core structure and the regulatory NH2-terminal variable region.

机译：肌钙蛋白T核心结构和调节性NH2末端可变区。

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摘要

The conserved central and COOH-terminal regions of troponin T (TnT) interact with troponin C, troponin I, and tropomyosin to regulate striated muscle contraction. Phylogenic data show that the NH2-terminal region has evolved as an addition to the conserved core structure of TnT. This NH2-terminal region does not bind other thin filament proteins, and its sequence is hypervariable between fiber type and developmental isoforms. Previous studies have demonstrated that NH2-terminal modifications alter the COOH-terminal conformation of TnT and thin filament Ca2+-activation, yet the functional core structure of TnT and the mechanism of NH2-terminal modulation are not well understood. To define the TnT core structure and investigate the regulatory role of the NH2-terminal variable region, we investigated two classes of model TnT molecules: (1) NH2-terminal truncated cardiac TnT and (2) chimera proteins consisting of an acidic or basic skeletal muscle TnT NH2-terminus spliced to the cardiac TnT core. Deletion of the TnT hypervariable NH2-terminus preserved binding to troponin I and tropomyosin and sustained cardiac muscle contraction in the heart of transgenic mice. Further deletion of the conserved central region diminished binding to tropomyosin. The reintroduction of differently charged NH2-terminal domains in the chimeric molecules produced long-range conformational changes in the central and COOH-terminal regions to alter troponin I and tropomyosin binding. Similar NH2-terminal charge effects are demonstrated in naturally occurring cardiac TnT isoforms, indicating a physiological significance. These results suggest that the hypervariable NH2-terminal region modulates the conformation and function of the TnT core structure to fine-tune muscle contractility.
机译：保守的肌钙蛋白T（TnT）的中央和COOH末端区域与肌钙蛋白C，肌钙蛋白I和原肌球蛋白相互作用，调节横纹肌的收缩。系统发育数据表明，NH2末端区域已进化为TnT保守核心结构的补充。该NH 2末端区域不结合其他细丝蛋白，并且其序列在纤维类型和发育同工型之间是高度可变的。以前的研究表明，NH2末端修饰会改变TnT的COOH末端构象和细丝Ca2 +活化，但是TnT的功能核心结构和NH2末端调节的机制尚不清楚。为了定义TnT核心结构并研究NH2末端可变区的调节作用，我们研究了两类模型TnT分子：（1）NH2末端截短的心脏TnT和（2）由酸性或碱性骨骼组成的嵌合蛋白。肌肉TnT NH2末端剪接至心脏TnT核心。 TnT高变NH2-末端的删除保留了与肌钙蛋白I和原肌球蛋白的结合，并在转基因小鼠的心脏中维持了心肌的持续收缩。保守中心区的进一步缺失减少了与原肌球蛋白的结合。嵌合分子中不同电荷的NH2末端结构域的重新引入在中央和COOH末端区域产生了远程构象变化，从而改变了肌钙蛋白I和原肌球蛋白的结合。在天然存在的心脏TnT同工型中证明了相似的NH2末端电荷效应，表明其生理意义。这些结果表明，高变NH 2末端区域调节TnT核心结构的构象和功能，以微调肌肉收缩力。

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