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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >DNA bending and unbending by MutS govern mismatch recognition and specificity
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DNA bending and unbending by MutS govern mismatch recognition and specificity

机译：MutS的DNA弯曲和弯曲控制错配识别和特异性

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摘要

DNA mismatch repair is central to the maintenance of genomic stability. It is initiated by the recognition of base-base mismatches and insertion/deletion loops by the family of MutS proteins. Subsequently, ATP induces a unique conformational change in the MutS-mismatch complex but not in the MutS-homoduplex complex that sets off the cascade of events that leads to repair. To gain insight into the mechanism by which MutS discriminates between mismatch and homoduplex DNA, we have examined the conformations of specific and nonspecific MutS-DNA complexes by using atomic force microscopy. Interestingly, MutS-DNA complexes exhibit a single population of conformations, in which the DNA is bent at homoduplex sites, but two populations of conformations, bent and unbent, at mismatch sites. These results suggest that the specific recognition complex is one in which the DNA is unbent. Combining our results with existing biochemical and crystallo-graphic data leads us to propose that MutS: (ⅰ) binds to DNA nonspecifically and bends it in search of a mismatch; (ⅱ) on specific recognition of a mismatch, undergoes a conformational change to an initial recognition complex in which the DNA is kinked, with interactions similar to those in the published crystal structures; and (ⅲ) finally undergoes a further conformational change to the ultimate recognition complex in which the DNA is unbent. Our results provide a structural explanation for the long-standing question of how MutS achieves mismatch repair specificity.
机译：DNA错配修复对于维持基因组稳定性至关重要。它是由MutS蛋白家族识别碱基错配和插入/缺失环而引发的。随后，ATP诱导MutS-错配复合体发生独特的构象变化，但不会引起MutS-homoduplex复合体发生独特的构象变化，从而引发导致修复的一系列事件。为了深入了解MutS区分错配和同源双链DNA的机制，我们使用原子力显微镜检查了特异性和非特异性MutS-DNA复合物的构象。有趣的是，MutS-DNA复合物表现出单一的构象群体，其中DNA在同源双链体位点弯曲，但是在错配位点有两个弯曲且未弯曲的构象群体。这些结果表明，特异性识别复合物是DNA未弯曲的复合物。将我们的结果与现有的生化和晶体学数据相结合，我们提出MutS：（ⅰ）与DNA非特异性结合并弯曲以寻找错配； （ⅱ）对错配的特异性识别，使初始识别复合体发生构象变化，其中DNA扭结，相互作用类似于已公开的晶体结构中的相互作用； （ⅲ）最后对未结合DNA的最终识别复合物进行进一步的构象变化。我们的结果为MutS如何实现错配修复特异性这一长期存在的问题提供了结构性解释。

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