Li Xiaolong, Li Bo, Li Jun, Yang Mingyuan, Bai Yushu, Chen Kai, Chen Ziqiang, Mao Ningfang
Department of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Orthopedics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Mol Biosci. 2022 Dec 19;9:1104942. doi: 10.3389/fmolb.2022.1104942. eCollection 2022.
Calcium (Ca) signaling plays an important role in the regulation of many cellular functions. Ca-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca 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 Ca-bound and-unbound states to reveal the importance of Ca. MD simulations revealed that removal of Ca 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 Ca-unbound state. Structural analysis further revealed that Ca 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 Ca in physiological processes.
钙（Ca）信号传导在许多细胞功能的调节中起着重要作用。钙结合蛋白钙调蛋白（CaM）是钙功能的主要效应器。Ca/CaM与死亡相关蛋白激酶1（DAPK1）结合以调节细胞内信号通路。然而，Ca对DAPK1-CaM相互作用的构象动力学影响的潜在机制仍不清楚。在这里，我们对结合钙和未结合钙状态下的DAPK1-CaM复合物进行了大规模分子动力学（MD）模拟，以揭示Ca的重要性。MD模拟表明，去除Ca会增加DAPK1和CaM之间的反相关域间运动，从而削弱DAPK1-CaM相互作用。结合自由能计算验证了在未结合Ca状态下DAPK1-CaM相互作用的减弱。结构分析进一步表明，去除Ca会导致DAPK1-CaM界面处发生显著的构象变化，特别是来自CaM的α1、α2、α4、α6和α7螺旋以及来自DAPK1的碱性环和磷酸结合环。这些结果可能有助于理解Ca在生理过程中的生物学作用。
