A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease.
A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease.
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DOI：
10.1038/ncomms14959
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发表时间：
2017-05-03
影响因子：
16.6
通讯作者：
Yin YW
中科院分区：
文献类型：
--
作者：
Szymanski MR;Yu W;Gmyrek AM;White MA;Molineux IJ;Lee JC;Yin YW
人外显子(HEXOG)是一种5‘端外切核酸酶，在线粒体DNA修复中起着至关重要的作用，属于非特异性核酸酶家族，包括细胞凋亡性内切酶endog。在这里，我们报告了hEXOG的生化和结构研究，包括其载脂蛋白形式的结构和分别在1.81和1.85 á分辨率下与DNA形成的络合物。翼结构域，在其他ββα-Me成员中不存在，抑制内切酶活性，但赋予hEXOG强大的5‘-dsDNA外切酶活性，使用固有的’卷尺‘精确地切除二核苷酸。对称的apo hEXOG同源二聚体与DNA结合后变得不对称，为底物DNA如何结合到一个活性部位以变构方式调节另一个活性部位的活性提供了结构基础。HEXOG的这些性质提示了线粒体BER的一条途径，该途径为随后的DNA聚合酶γ的缺口填充合成提供了最佳底物。人类Exog对线粒体DNA修复至关重要。在这里，作者提出了hEXOG的载脂蛋白形式和DNA复合体的晶体结构，并提出了产生线粒体碱基切除修复的最佳底物的“卷尺”活性。
Human EXOG (hEXOG) is a 5′-exonuclease that is crucial for mitochondrial DNA repair; the enzyme belongs to a nonspecific nuclease family that includes the apoptotic endonuclease EndoG. Here we report biochemical and structural studies of hEXOG, including structures in its apo form and in a complex with DNA at 1.81 and 1.85 Å resolution, respectively. A Wing domain, absent in other ββα-Me members, suppresses endonuclease activity, but confers on hEXOG a strong 5′-dsDNA exonuclease activity that precisely excises a dinucleotide using an intrinsic ‘tape-measure'. The symmetrical apo hEXOG homodimer becomes asymmetrical upon binding to DNA, providing a structural basis for how substrate DNA bound to one active site allosterically regulates the activity of the other. These properties of hEXOG suggest a pathway for mitochondrial BER that provides an optimal substrate for subsequent gap-filling synthesis by DNA polymerase γ. Human EXOG is crucial for mitochondrial DNA repair. Here the authors present the crystal structures of hEXOG in apo form and as DNA complex and suggest a `tape-measure' activity to generate optimal substrates for mitochondrial base excision repair.