Berger Florian, Hudspeth A J
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.
Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
PLoS Comput Biol. 2017 May 26;13(5):e1005566. doi: 10.1371/journal.pcbi.1005566. eCollection 2017 May.
Myosin Ic is thought to be the principal constituent of the motor that adjusts mechanical responsiveness during adaptation to prolonged stimuli by hair cells, the sensory receptors of the inner ear. In this context myosin molecules operate neither as filaments, as occurs in muscles, nor as single or few molecules, as characterizes intracellular transport. Instead, myosin Ic molecules occur in a complex cluster in which they may exhibit cooperative properties. To better understand the motor's remarkable function, we introduce a theoretical description of myosin Ic's chemomechanical cycle based on experimental data from recent single-molecule studies. The cycle consists of distinct chemical states that the myosin molecule stochastically occupies. We explicitly calculate the probabilities of the occupancy of these states and show their dependence on the external force, the availability of actin, and the nucleotide concentrations as required by thermodynamic constraints. This analysis highlights that the strong binding of myosin Ic to actin is dominated by the ADP state for small external forces and by the ATP state for large forces. Our approach shows how specific parameter values of the chemomechanical cycle for myosin Ic result in behaviors distinct from those of other members of the myosin family. Integrating this single-molecule cycle into a simplified ensemble description, we predict that the average number of bound myosin heads is regulated by the external force and nucleotide concentrations. The elastic properties of such an ensemble are determined by the average number of myosin cross-bridges. Changing the binding probabilities and myosin's stiffness under a constant force results in a mechanical relaxation which is large enough to account for fast adaptation in hair cells.
肌球蛋白Ic被认为是内耳感觉感受器毛细胞在适应长时间刺激过程中调节机械反应性的运动蛋白的主要成分。在这种情况下，肌球蛋白分子既不像肌肉中那样以细丝形式运作，也不像细胞内运输那样以单个或少数分子形式运作。相反，肌球蛋白Ic分子以复杂的簇状形式存在，在其中它们可能表现出协同特性。为了更好地理解这种运动蛋白的显著功能，我们基于最近单分子研究的实验数据，引入了对肌球蛋白Ic化学机械循环的理论描述。该循环由肌球蛋白分子随机占据的不同化学状态组成。我们明确计算了这些状态的占据概率，并表明它们如何根据热力学限制依赖于外力、肌动蛋白的可用性和核苷酸浓度。该分析突出表明，对于小外力，肌球蛋白Ic与肌动蛋白的强结合由ADP状态主导，而对于大外力则由ATP状态主导。我们的方法展示了肌球蛋白Ic化学机械循环的特定参数值如何导致与肌球蛋白家族其他成员不同的行为。将这个单分子循环整合到一个简化的整体描述中，我们预测结合的肌球蛋白头部的平均数量受外力和核苷酸浓度调节。这样一个整体的弹性特性由肌球蛋白横桥的平均数量决定。在恒定力作用下改变结合概率和肌球蛋白的刚度会导致足够大的机械松弛，足以解释毛细胞中的快速适应。
