Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase.
Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase.
复制标题
钙在钙调蛋白调节的死亡相关蛋白激酶变构调节中的作用的机制见解
DOI：
10.3389/fmolb.2022.1104942
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
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作者：
钙（Ca2+）信号在许多细胞功能的调控中起着重要作用。钙结合蛋白钙调蛋白（CaM）是钙功能的主要效应因子。Ca2+/CaM结合死亡相关蛋白激酶1 （DAPK1）调节细胞内信号通路。然而，Ca2+对DAPK1 - CaM相互作用构象动力学影响的机制尚不清楚。在这里，我们对Ca2+结合和非结合状态的DAPK1 - CaM复合体进行了大规模的分子动力学（MD）模拟，以揭示Ca2+的重要性。MD模拟显示，Ca2+的去除增加了DAPK1和CaM之间的反相关结构域间运动，从而减弱了DAPK1 - CaM的相互作用。结合自由能计算证实了Ca2+非结合状态下DAPK1 - CaM相互作用的降低。结构分析进一步表明，Ca2+去除引起了DAPK1 - CaM界面的明显构象变化，特别是CaM的α1、α2、α4、α6和α7螺旋以及DAPK1的碱性环和磷酸结合环的构象变化。这些结果可能有助于了解Ca2+在生理过程中的生物学作用。
Calcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca2+/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca2+ on the conformational dynamics of the DAPK1−CaM interactions is still unclear. Here, we performed large-scale molecular dynamics (MD) simulations of the DAPK1−CaM complex in the Ca2+-bound and-unbound states to reveal the importance of Ca2+. MD simulations revealed that removal of Ca2+ increased the anti-correlated inter-domain motions between DAPK1 and CaM, which weakened the DAPK1−CaM interactions. Binding free energy calculations validated the decreased DAPK1−CaM interactions in the Ca2+-unbound state. Structural analysis further revealed that Ca2+ removal caused the significant conformational changes at the DAPK1−CaM interface, especially the helices α1, α2, α4, α6, and α7 from the CaM and the basic loop and the phosphate-binding loop from the DAPK1. These results may be useful to understand the biological role of Ca2+ in physiological processes.
钙调蛋白与 PI3K p85 调节亚基的 c/nSH2 结构域之间相互作用的计算见解：钙调蛋白激活 PI3K 的意义
影响因子：
5.6
作者：
Ni D;Liu D;Zhang J;Lu S
通讯作者：
Lu S
影响因子：
2.9
作者：
Lawrenz, Morgan;Wereszczynski, Jeff;Amaro, Rommie;Walker, Ross;Roitberg, Adrian;McCammon, J. Andrew
通讯作者：
McCammon, J. Andrew
对抑制剂选择性的机理对深色激酶STK17B对其高同源性STK17A的机制。
DOI：
10.3390/molecules27144655
发表时间：
2022-07-21
期刊：
Molecules (Basel, Switzerland)
影响因子：
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