The myosin head transforms chemical energy from ATP hydrolysis into mechanical work to generate isometric force or to drive muscle shortening. During the power stroke, small changes in the catalytic ATPase site of the actin-bound myosin head are coupled to tilting of the light-chain binding domain relative to the catalytic domain. In this mechanism distortion of an elastic element within the actomyosin complex is essential for strain to develop prior to movement.We have studied missense mutations naturally occurring in Familial Hypertrophic Cardiomyopathy (FHC) to test molecular mechanisms and functional roles of specific domains of the myosin head. Slow soleus muscle fibers (expressing the ventricular myosin isoform) of FHC-patients were used for these studies. Previously we found that mutation R723G which is located in the converter domain of the myosin head increases active force and resistance to elastic distortion (fiber stiffness) during contraction, relaxation, and rigor, while cross-bridge cycling kinetics were unchanged. This indicated that the converter is the part of the actomyosin complex where most of the elastic distortion occurs.We now included mutation R453C located near the nucleotide binding pocket of myosin in our functional studies. This mutation was found to also increase active force, however, without affecting fiber stiffness. Instead, mutation R453C increased fiber ATPase activity and the rate constant of force redevelopment (kredev) significantly, which were unchanged by mutation R723G. Thus, both FHC mutations cause force enhancement in muscle fibers from FHC patients, however, by distinctly different mechanisms. R723G affects resistance to elastic distortion of the myosin head while R453C alters cross-bridge cycling kinetics. The data underline the different functional roles of the domains within the myosin head and point to an involvement of residue R453 in human ventricular myosin ATPase activity.

中文翻译：

---

肌球蛋白头域突变 R723G 和 R453C 增强力的不同分子机制

肌球蛋白头将来自 ATP 水解的化学能转化为机械功以产生等长力或驱动肌肉缩短。在动力冲程期间，肌动蛋白结合肌球蛋白头部的催化 ATP 酶位点的微小变化与轻链结合域相对于催化域的倾斜有关。在这种机制中，肌动球蛋白复合物中弹性元件的变形对于运动前应变的发展至关重要。 我们研究了家族性肥厚性心肌病 (FHC) 中自然发生的错义突变，以测试肌球蛋白头部特定结构域的分子机制和功能作用. FHC 患者的慢比目鱼肌纤维（表达心室肌球蛋白同种型）用于这些研究。以前我们发现位于肌球蛋白头部转换器域的突变 R723G 在收缩、松弛和严密期间增加了主动力和对弹性变形（纤维刚度）的抵抗力，而跨桥循环动力学没有变化。这表明转换器是肌动球蛋白复合物的大部分弹性变形发生的部分。我们现在在我们的功能研究中包括位于肌球蛋白核苷酸结合口袋附近的突变 R453C。然而，发现这种突变也会增加主动力，而不会影响纤维刚度。相反，突变 R453C 显着增加了纤维 ATP 酶活性和力再发展速率常数 (kredev)，而突变 R723G 没有改变这些。因此，两种 FHC 突变都会导致 FHC 患者肌肉纤维的力量增强，然而，通过截然不同的机制。R723G 影响对肌球蛋白头部弹性变形的抵抗力，而 R453C 改变跨桥循环动力学。数据强调了肌球蛋白头部内结构域的不同功能作用，并指出残基 R453 参与人心室肌球蛋白 ATP 酶活性。