Mechanically induced titin kinase activation studied by force-probe molecular dynamics simulations
Mechanically induced titin kinase activation studied by force-probe molecular dynamics simulations
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DOI：
10.1529/biophysj.104.052423
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发表时间：
2005-02-01
影响因子：
3.4
通讯作者：
Grubmüller, H
中科院分区：
文献类型：
--
作者：
Gräter, F;Shen, JH;Grubmüller, H
在肌肉细胞中将机械应力转化为生化信号需要一个力传感器。弹性肌蛋白Titin的催化结构域Titin激酶已被认为是一个候选。它的激活需要主要的构象变化，从而暴露其活性位点。在这里，力探针分子动力学模拟被用来深入了解张力诱导的激活机制。我们发现在没有完整的结构域展开的情况下，催化位点的顺序机械诱导打开的证据。我们的结果表明，两个末端β -片的破裂是主要的展开步骤。c端相对于n端β片的低阻力归因于它们的不同几何形状。随后的自抑制尾部重排导致活性位点暴露，这是titin激酶活性所必需的。这些结果支持了titin激酶作为力传感器的假设。
The conversion of mechanical stress into a biochemical signal in a muscle cell requires a force sensor. Titin kinase, the catalytic domain of the elastic muscle protein titin, has been suggested as a candidate. Its activation requires major conformational changes resulting in the exposure of its active site. Here, force-probe molecular dynamics simulations were used to obtain insight into the tension-induced activation mechanism. We find evidence for a sequential mechanically induced opening of the catalytic site without complete domain unfolding. Our results suggest the rupture of two terminal beta-sheets as the primary unfolding steps. The low force resistance of the C-terminal relative to the N-terminal beta-sheet is attributed to their different geometry. A subsequent rearrangement of the autoinhibitory tail is seen to lead to the exposure of the active site, as is required for titin kinase activity. These results support the hypothesis of titin kinase as a force sensor.