Mukherjee Shayantani, Law Sean M, Feig Michael
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
Biophys J. 2009 Mar 4;96(5):1707-20. doi: 10.1016/j.bpj.2008.10.071.
Postreplication DNA mismatch repair is essential for maintaining the integrity of genomic information in prokaryotes and eukaryotes. The first step in mismatch repair is the recognition of base-base mismatches and insertions/deletions by bacterial MutS or eukaryotic MSH2-MSH6. Crystal structures of both proteins bound to mismatch DNA reveal a similar molecular architecture but provide limited insight into the detailed molecular mechanism of long-range allostery involved in mismatch recognition and repair initiation. This study describes normal-mode calculations of MutS and MSH2-MSH6 with and without DNA. The results reveal similar protein flexibilities and suggest common dynamic and functional characteristics. A strongly correlated motion is present between the lever domain and ATPase domains, which suggests a pathway for long-range allostery from the N-terminal DNA binding domain to the C-terminal ATPase domains, as indicated by experimental studies. A detailed analysis of individual low-frequency modes of both MutS and MSH2-MSH6 shows changes in the DNA-binding domains coupled to the ATPase sites, which are interpreted in the context of experimental data to arrive at a complete molecular-level mismatch recognition cycle. Distinct conformational states are proposed for DNA scanning, mismatch recognition, repair initiation, and sliding along DNA after mismatch recognition. Hypotheses based on the results presented here form the basis for further experimental and computational studies.
复制后DNA错配修复对于维持原核生物和真核生物基因组信息的完整性至关重要。错配修复的第一步是细菌MutS或真核生物MSH2 - MSH6识别碱基错配和插入/缺失。与错配DNA结合的这两种蛋白质的晶体结构揭示了相似的分子结构，但对于错配识别和修复起始过程中涉及的远程变构详细分子机制提供的见解有限。本研究描述了有DNA和无DNA情况下MutS和MSH2 - MSH6的正常模式计算。结果揭示了相似的蛋白质灵活性，并表明了共同的动态和功能特征。杠杆结构域和ATP酶结构域之间存在强烈的相关运动，这表明了从N端DNA结合结构域到C端ATP酶结构域的远程变构途径，正如实验研究所表明的那样。对MutS和MSH2 - MSH6各自低频模式的详细分析显示，DNA结合结构域的变化与ATP酶位点相关，结合实验数据对其进行解释，从而得出完整的分子水平错配识别循环。针对DNA扫描、错配识别、修复起始以及错配识别后沿DNA滑动提出了不同的构象状态。基于此处呈现结果的假设构成了进一步实验和计算研究的基础。
