Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity.
Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity.
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DOI：
10.1016/j.bpj.2009.04.012
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发表时间：
2009-06
影响因子：
3.4
通讯作者：
S. Mukherjee;M. Feig
中科院分区：
文献类型：
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作者：
S. Mukherjee;M. Feig
复制后DNA错配修复由真核蛋白MSH 2-MSH 6或原核蛋白MutS启动，两者均显示出整体保守的结构和功能。MSH 2-MSH 6和MutS结合到错配DNA的晶体结构揭示了钳和杠杆结构域的闭合结构，其表现出与弯曲的DNA骨架的强接触。在不存在DNA的情况下对人类MSH 2-MSH 6蛋白的长时间分子动力学模拟显示了蛋白质的改变的构象，其反映了蛋白质在与DNA结合之前的状态。MSH 6和MSH 2的钳和杠杆结构域以不对称和戏剧性的方式打开。在不存在DNA的情况下，钳和杠杆结构域的打开与ATP酶结构域的变化相关联，这解释了在无DNA的MSH 2-MSH 6中实验观察到的ATP酶活性降低，并说明了DNA结合和ATP酶活性之间的变构偶联。
Postreplication DNA mismatch repair is initiated by the eukaryotic protein MSH2-MSH6 or the prokaryotic protein MutS, both showing overall conserved structure and functionality. Crystal structures of MSH2-MSH6 and MutS bound to the mismatch DNA reveal a closed architecture of the clamp and the lever domains exhibiting strong contacts with the bent DNA backbone. Long molecular dynamics simulations of the human MSH2-MSH6 protein in the absence of a DNA show an altered conformation of the protein that reflects the protein's state before binding to DNA. The clamp and the lever domains of both MSH6 and MSH2 open in an asymmetric and dramatic fashion. The opening of the clamp and the lever domains in the absence of DNA is coupled to changes in the ATPase domains, which explains the experimentally observed diminished ATPase activity in DNA-free MSH2-MSH6 and illustrates the allosteric coupling between DNA binding and ATPase activity.