The DNA mismatch repair (MMR) pathway removes errors that appear during genome replication. MutS is the primary mismatch sensor and forms an asymmetric dimer that encircles DNA to bend it to scan for mismatches. The mechanism utilized to load DNA into the central tunnel was unknown and the origin of the force required to bend DNA was unclear. We show that, in absence of DNA, MutS forms a symmetric dimer wherein a gap exists between the monomers through which DNA can enter the central tunnel. The comparison with structures of MutS–DNA complexes suggests that the mismatch scanning monomer (B_m) will move by nearly 50 Å to associate with the other monomer (A_m). Consequently, the N-terminal domains of both monomers will press onto DNA to bend it. The proposed mechanism of toroid formation evinces that the force required to bend DNA arises primarily due to the movement of B_m and hence, the MutS dimer acts like a pair of pliers to bend DNA. We also shed light on the allosteric mechanism that influences the expulsion of adenosine triphosphate from A_m on DNA binding. Overall, this study provides mechanistic insight regarding the primary event in MMR i.e. the assembly of the MutS–DNA complex.

中文翻译：

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错配传感器蛋白在DNA周围形成环面的机理

DNA错配修复（MMR）途径可消除基因组复制过程中出现的错误。MutS是主要的失配传感器，它形成一个不对称的二聚体，环绕着DNA使其弯曲以扫描失配。将DNA加载到中央通道中的机制尚不清楚，弯曲DNA所需的力的来源尚不清楚。我们表明，在没有DNA的情况下，MutS会形成一个对称的二聚体，其中单体之间存在间隙，DNA可以通过该间隙进入中央通道。与MutS–DNA复合物的结构比较表明，错配扫描单体（B _m）将移动近50Å以与其他单体（A _m）。因此，两种单体的N末端结构域都将压在DNA上使其弯曲。提出的环形形成机理表明，弯曲DNA所需的力主要是由于B _m的运动而产生的，因此MutS二聚体的作用就像一对钳子来弯曲DNA。我们还阐明了影响DNA结合从A _m排出三磷酸腺苷的变构机制。总体而言，这项研究提供了有关MMR中主要事件（即MutS-DNA复合体的组装）的机制性见解。