Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states
Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states
复制标题
DOI：
10.1085/jgp.201812188
复制
发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Rynkiewicz, Michael J.
中科院分区：
文献类型：
--
作者：
Kiani, Farooq A.;Lehman, William;Rynkiewicz, Michael J.
肌肉收缩后，肌球蛋白的桥头在松弛时从细丝上分离。跨桥-细丝相互作用的结构和动力学数据表明，当肌球蛋白分离时，原肌球蛋白在F-肌动蛋白上的位置偏向于封闭或封闭状态。目前尚不清楚是原肌球蛋白和肌球蛋白交叉桥头之间的结构联系，还是原肌球蛋白和Cat(2+)自由肌钙蛋白推动了这一过程，或者原肌球蛋白的运动是否在能量上独立于肌球蛋白和肌钙蛋白的影响。在这里，我们提供了原肌球蛋白在肌钙蛋白/不含肌球蛋白的F-肌动蛋白上的动力学数据，表明原肌球蛋白在肌动蛋白上从开放状态向封闭或封闭状态移动。为了跟踪原肌球蛋白本身在F-肌动蛋白上固有的转变，我们从阻断、开放和中间状态模型开始进行MD模拟，并在没有肌球蛋白和肌钙蛋白的情况下跟踪原肌球蛋白在F-肌动蛋白表面的变化。这些MD模拟将原肌球蛋白保持在索状构象中，包括原肌球蛋白重叠结构域，同时允许原肌球蛋白保持其大部分运动自由。原肌球蛋白显示出相当大的方位运动，远离开放状态，朝向F-肌动蛋白上更有利的封闭B状态位置的周围。相反，几乎没有观察到远离B态位置的运动。我们的结果与以前基于原肌球蛋白刚体移位所确定的静电相互作用能景观的预测是一致的。他们支持这样的观点，即在没有肌球蛋白的情况下，即当肌球蛋白的跨桥与肌动蛋白分离时，原肌球蛋白的封闭或关闭状态在能量上是有利的，而白色则不是。
After muscle contraction, myosin cross-bridge heads detach from thin actin filaments during relaxation. Structural and kinetic data of cross-bridge-thin filament interactions have shown that tropomyosin's position on F-actin is biased toward the blocked or closed states when myosin detaches. It is not clear if structural linkages between tropomyosin and myosin cross-bridge heads, or tropomyosin and Cat(2+)-free troponin, drive the process or whether tropomyosin movement is energetically independent of myosin and troponin influence. Here we provide in silico data about tropomyosin dynamics on troponin/myosin-free F-actin indicating that tropomyosin moves from the open state toward blocked- or closed-state positions on actin. To follow transitions inherent to tropomyosin itself on F-actin, we performed MD simulations initiated from the blocked-, open-, and intermediate-state models and followed tropomyosin over the surface of F-actin in the absence of myosin and troponin. These MD simulations maintain tropomyosin in a cable-like conformation, including the tropomyosin overlap domain, while allowing tropomyosin to retain most of its motional freedom. Tropomyosin shows considerable azimuthal movement away from the open state toward the surrounds of a more energetically favorable blocked B-state position over F-actin. In contrast, little movement away from the B-state location is observed. Our results are consistent with previous predictions based on electrostatic interaction energy landscapes determined by rigid-body translocation of tropomyosin. They support the view that in the absence of myosin, i.e., when myosin cross-bridges detach from actin, the blocked- or closed-state positions of tropomyosin are energetically favored, white the open state is not.