In the heart, mutations in the TPM1 gene encoding the α-isoform of tropomyosin lead, in particular, to the development of hypertrophic and dilated cardiomyopathies. We compared the effects of hypertrophic, D175N and E180G, and dilated, E40K and E54K, cardiomyopathy mutations in TPM1 gene on the properties of single actin–myosin interactions and the characteristics of the calcium regulation in an ensemble of myosin molecules immobilised on a glass surface and interacting with regulated thin filaments. Previously, we showed that at saturating Ca²⁺ concentration the presence of Tpm on the actin filament increases the duration of the interaction. Here, we found that the studied Tpm mutations differently affected the duration: the D175N mutation reduced it compared to WT Tpm, while the E180G mutation increased it. Both dilated mutations made the duration of the interaction even shorter than with F-actin. The duration of the attached state of myosin to the thin filament in the optical trap did not correlate to the sliding velocity of thin filaments and its calcium sensitivity in the in vitro motility assay. We suppose that at the level of the molecular ensemble, the cooperative mechanisms prevail in the manifestation of the effects of cardiomyopathy-associated mutations in Tpm.

中文翻译：

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原肌球蛋白与心肌病相关的突变在单分子和集合水平上不同地影响肌动蛋白-肌球蛋白的相互作用。

在心脏中，编码原肌球蛋白α-亚型的TPM1基因突变尤其导致肥大性和扩张型心肌病的发展。我们比较了TPM1基因中的肥大性D175N和E180G以及扩张型E40K和E54K心肌病突变对单个肌动蛋白-肌球蛋白相互作用的特性以及固定在玻璃表面上的一组肌球蛋白分子的钙调节特性的影响并与调节的细丝相互作用。之前，我们表明饱和Ca ²⁺浓缩后，肌动蛋白丝上存在Tpm会增加相互作用的持续时间。在这里，我们发现研究的Tpm突变对持续时间的影响不同：与WT Tpm相比，D175N突变减少了突变，而E180G突变增加了突变。两种扩张的突变都使得相互作用的持续时间甚至短于F-肌动蛋白。肌球蛋白在光阱中附着于细丝的状态的持续时间与细丝的滑动速度及其在体外运动性测定中的钙敏感性无关。我们假设在分子整体水平上，合作机制在与心肌病相关的Tpm突变的影响中占主导地位。