The myosin duty ratio tunes the calcium sensitivity and cooperative activation of the thin filament.
The myosin duty ratio tunes the calcium sensitivity and cooperative activation of the thin filament.
复制标题
肌球蛋白占空比调节细丝的钙敏感性和协同激活。
DOI：
10.1021/bi400262h
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发表时间：
2013
期刊：
影响因子：
2.9
通讯作者：
Baker,JoshE
中科院分区：
文献类型：
--
作者：
Webb,Milad;JacksonJr,DelR;Stewart,TravisJ;Dugan,SamuelP;Carter,MichaelS;Cremo,ChristineR;Baker,JoshE
在横纹肌中，钙与细丝（TF）调节复合体的结合激活了肌动蛋白-肌球蛋白atp酶的活性，而肌动蛋白-肌球蛋白动力学反过来调节了TF的激活。然而，肌动蛋白-肌球蛋白动力学对TF激活的钙敏感性（pCa50）和协同性（nH）的影响的定量描述是缺乏的。假设TF结构转变和TF -肌球蛋白结合转变是不可分割的耦合，我们提出了Kad等人建立的原则[Kad， N., et al. (2005)Proc.]。国家的。学会科学。[J] .中国生物医学工程学报，2009,32(2):489 - 491。医学杂志。建立了一个简单的TF调节模型，该模型预测pca50随占空比线性变化，并且其最大接近生理占空比。利用体外运动测定TF滑动速度的钙敏感性，我们测量了pca50和nhat不同的肌球蛋白密度和atp酶抑制剂的存在。观察到肌凝蛋白密度和肌动蛋白-肌凝蛋白占空比对pca50和n4的影响与我们的模型预测一致。在横纹肌中，pca50必须与细胞质钙浓度匹配，并且最大限度地优化钙响应性。我们的研究结果表明，pca50和nh可以通过tf -肌球蛋白atp酶动力学进行可预测的调节，并且改变atp酶动力学的药物和疾病状态可以通过其对钙敏感性的影响，改变肌肉收缩的效率。
In striated muscle, calcium binding to the thin filament (TF) regulatory complex activates actin–myosin ATPase activity, and actin–myosin kinetics in turn regulates TF activation. However, a quantitative description of the effects of actin–myosin kinetics on the calcium sensitivity (pCa50) and cooperativity (nH) of TF activation is lacking. With the assumption that TF structural transitions and TF–myosin binding transitions are inextricably coupled, we advanced the principles established by Kad et al. [Kad, N., et al. (2005)Proc. Natl. Acad. Sci. U.S.A. 102, 16990–16995] and Sich et al. [Sich, N. M., et al. (2011)J. Biol. Chem. 285, 39150–39159] to develop a simple model of TF regulation, which predicts that pCa50varies linearly with duty ratio and thatnHis maximal near physiological duty ratios. Usingin vitromotility to determine the calcium sensitivity of TF sliding velocities, we measured pCa50andnHat different myosin densities and in the presence of ATPase inhibitors. The observed effects of myosin density and actin–myosin duty ratio on pCa50andnHare consistent with our model predictions. In striated muscle, pCa50must match cytosolic calcium concentrations and a maximalnHoptimizes calcium responsiveness. Our results indicate that pCa50andnHcan be predictably tuned through TF–myosin ATPase kinetics and that drugs and disease states that alter ATPase kinetics can, through their effects on calcium sensitivity, alter the efficiency of muscle contraction.