Detailed regulatory mechanism of the interaction between ZO-1 PDZ2 and connexin43 revealed by MD simulations.
Detailed regulatory mechanism of the interaction between ZO-1 PDZ2 and connexin43 revealed by MD simulations.
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MD模拟揭示ZO-1 PDZ2与Connexin43相互作用的详细调控机制
DOI：
10.1371/journal.pone.0021527
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Xiao F;Weng J;Fan K;Wang W
间隙连接蛋白connexin43 （Cx43）通过其c端尾部结合到Zonula occludens-1 （ZO-1）的第二个PDZ结构域，介导间隙连接斑块大小和动力学的调节。生化研究表明，Cx43的c端12个残基对于ZO-1 PDZ2的结合是必要和充分的，而肽的Ser（-9）和Ser（-10）残基的磷酸化会破坏这种结合。然而，实验只解决了ZO-1 PDZ2与connexin43较短的9aa肽配合物的晶体结构。通过分子动力学模拟和自由能计算，研究了ZO-1 PDZ2与短、长、磷酸化的Cx43肽之间的相互作用。与PDZ2结合的短肽表现出较大的结构变化，而上游三个残基的延伸稳定了肽的构象并增强了相互作用。丝氨酸（-9）的磷酸化显著削弱了结合，导致肽的构象柔韧性。ZO-1 PDZ2的Glu210被发现是Cx43结合和磷酸化诱导解离的关键调控点。
The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation.
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