Abstract:
Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.
摘要:
心肌具有其永远不能休息的独特性质;所有心肌细胞随着每次心跳而收缩,这需要复杂的控制机制来调节心输出量以达到生理要求。钙浓度的变化调节细丝的活化。一个独立但有联系的机制调节粗丝的激活,释放了足够的肌球蛋白头来结合细丝,从而产生所需的力。粗丝含有额外的非肌球蛋白蛋白,肌球蛋白结合蛋白C和肌动蛋白,后者是将施加的张力传递给粗丝的蛋白质。这三种蛋白质如何相互作用以控制粗丝激活还知之甚少。这里,我们显示,使用缺乏外源药物的冷冻水合人心肌肌原纤维的3-D图像重建,粗丝的结构可提供三个水平的肌球蛋白激活,对应于每个429µrepeat中肌球蛋白头的三个冠。在一个皇冠上,肌球蛋白头几乎完全激活和紊乱。在另一个皇冠上,许多肌球蛋白头部不活跃,被命令成一个叫做交互头图案的结构。在第三个王冠上,肌球蛋白头部被排序为相互作用的头部图案,但是该基序的稳定性受肌球蛋白结合蛋白C的影响。我们认为这种控制层次解释了长度依赖性激活以及拉伸激活在心肌控制中的许多影响。