Molecular dynamics simulations of the cardiac troponin complex performed with FRET distances as restraints.
Molecular dynamics simulations of the cardiac troponin complex performed with FRET distances as restraints.
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DOI：
10.1371/journal.pone.0087135
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dong WJ
中科院分区：
文献类型：
--
作者：
Jayasundar JJ;Xing J;Robinson JM;Cheung HC;Dong WJ
心肌肌钙蛋白 (cTn) 是控制心肌激活和松弛的 Ca2+ 敏感分子开关。然而，开关机制的分子细节以及心肌肌钙蛋白 C (cTnC) 接收到的 Ca2+ 信号如何传递至心肌肌钙蛋白 I (cTnI) 仍然难以捉摸。为了揭示肌钙蛋白转换的结构细节，我们对心脏肌钙蛋白核心域复合物进行了整体福斯特共振能量转移（FRET）测量和分子动力学（MD）模拟。在无 Ca2+ 和饱和 Ca2+ 条件下，通过时间分辨 FRET 测量获得了 45 个残基间对的距离分布。在心肌肌钙蛋白核心域的 MD 模拟过程中，这些距离被纳入作为限制。与 Ca2+ 饱和结构相比，调节性 Ca2+ 的缺失扰乱了 cTnC N 结构域疏水口袋，该口袋呈现封闭构象。该事件部分揭示了 cTnI 调节区/开关。 Ca2+ 的缺失诱导了 D/E 连接子和 cTnI 抑制区的灵活性，并相对于肌钙蛋白核心结构域的其余部分旋转了 cTnC N 结构域。在饱和Ca2+存在下，上述现象不存在。我们假设 cTnI 调节区在 cTnC N 结构域疏水口袋内经历的二级结构扰动，加上 cTnC N 结构域的旋转，将控制 cTnI 移动结构域与肌动蛋白的相互作用。同时，cTnC N 结构域的旋转和 D/E 连接体刚性的扰动将控制 cTnI 抑制区域与肌动蛋白的相互作用，从而实现肌肉松弛。
Cardiac troponin (cTn) is the Ca2+-sensitive molecular switch that controls cardiac muscle activation and relaxation. However, the molecular detail of the switching mechanism and how the Ca2+ signal received at cardiac troponin C (cTnC) is communicated to cardiac troponin I (cTnI) are still elusive. To unravel the structural details of troponin switching, we performed ensemble Förster resonance energy transfer (FRET) measurements and molecular dynamic (MD) simulations of the cardiac troponin core domain complex. The distance distributions of forty five inter-residue pairs were obtained under Ca2+-free and saturating Ca2+ conditions from time-resolved FRET measurements. These distances were incorporated as restraints during the MD simulations of the cardiac troponin core domain. Compared to the Ca2+-saturated structure, the absence of regulatory Ca2+ perturbed the cTnC N-domain hydrophobic pocket which assumed a closed conformation. This event partially unfolded the cTnI regulatory region/switch. The absence of Ca2+, induced flexibility to the D/E linker and the cTnI inhibitory region, and rotated the cTnC N-domain with respect to rest of the troponin core domain. In the presence of saturating Ca2+ the above said phenomenon were absent. We postulate that the secondary structure perturbations experienced by the cTnI regulatory region held within the cTnC N-domain hydrophobic pocket, coupled with the rotation of the cTnC N-domain would control the cTnI mobile domain interaction with actin. Concomitantly the rotation of the cTnC N-domain and perturbation of the D/E linker rigidity would control the cTnI inhibitory region interaction with actin to effect muscle relaxation.
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