Potential impacts of the cardiac troponin I mobile domain on myofilament activation and relaxation.
Potential impacts of the cardiac troponin I mobile domain on myofilament activation and relaxation.
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心肌肌钙蛋白I移动结构域对肌丝激活和松弛的潜在影响。
DOI：
10.1016/j.yjmcc.2021.02.012
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发表时间：
2021-06
影响因子：
5
通讯作者：
Campbell SG
中科院分区：
文献类型：
--
作者：
Creso JG;Campbell SG
心肌细丝通过肌钙蛋白和原肌球蛋白(TM)的构象变化，以钙离子依赖的方式进行调节。一般认为，在低钙条件下，肌钙蛋白I(TnI)的抑制肽段(IP)与肌动蛋白结合，并使肌球蛋白上的TM位于肌球蛋白结合部位，以防止交叉桥的形成。最近，有证据表明TnI的C-末端移动结构域(MD)也与肌动蛋白结合，这使得情况变得更加复杂。本研究使用一个计算模型来研究假设TNI通过两个肌动蛋白结合结构域而不是一个结构域来调节TM运动的后果。首先，以TnI-IP作为唯一的调节域，建立了心脏细丝调节单元的16态模型。将其扩展到包括TNI-MD形成了一个24个州的模型。这些模型的比较表明，假设第二个肌动蛋白结合位点允许单个结构域与肌动蛋白的亲和力低于IP单独作用所需的亲和力。事实上，将IP和MD的肌动蛋白亲和力设置为单部位模型中IP假设的25%就足以实现完全相同的钙调节程度。我们还测试了24态模型在IP或MD中断的情况下表示稳态实验数据的能力。我们能够捕捉到几个属性的质变，这些属性与实验数据中看到的相匹配。最后，进行模拟以检验IP或MD中断对抽动动力学的影响。我们的结果表明，这两个区域都需要将舒张期跨桥活动保持在最低限度，并加速肌丝松弛。总体而言，我们的分析支持这样一种范式，即TnI的两个结构域与肌动蛋白具有中等的亲和力，共同完成对细丝的钙依赖调节。
The cardiac thin filament is regulated in a Ca2+-dependent manner through conformational changes of troponin and tropomyosin (Tm). It has been generally understood that under conditions of low Ca2+ the inhibitory peptide domain (IP) of troponin I (TnI) binds to actin and holds Tm over the myosin binding sites on actin to prevent crossbridge formation. More recently, evidence that the C-terminal mobile domain (MD) of TnI also binds actin has made for a more complex scenario. This study uses a computational model to investigate the consequences of assuming that TnI regulates Tm movement via two actin-binding domains rather than one. First, a 16-state model of the cardiac thin filament regulatory unit was created with TnI-IP as the sole regulatory domain. Expansion of this to include TnI-MD formed a 24-state model. Comparison of these models showed that assumption of a second actin-binding site allows the individual domains to have a lower affinity for actin than would be required for IP acting alone. Indeed, setting actin affinities of the IP and MD to 25% of that assumed for the IP in the single-site model was sufficient to achieve precisely the same degree of Ca2+ regulation. We also tested the 24-state model’s ability to represent steady-state experimental data in the case of disruption of either the IP or MD. We were able to capture qualitative changes in several properties that matched what was seen in the experimental data. Lastly, simulations were run to examine the effect of disruption of the IP or MD on twitch dynamics. Our results suggest that both domains are required to keep diastolic cross-bridge activity to a minimum and accelerate myofilament relaxation. Overall, our analyses support a paradigm in which two domains of TnI bind with moderate affinity to actin, working in tandem to complete Ca2+-dependent regulation of the thin filament.
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