Solution structure of the Zβ domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs
Solution structure of the Zβ domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs
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DOI：
10.1073/pnas.1014898107
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发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Jeon, Young Ho
中科院分区：
文献类型：
--
作者：
Kim, Kyungmin;Khayrutdinov, Bulat I.;Jeon, Young Ho
IFN-调节因子（DAI）的DNA依赖性激活剂，也称为DLM-1/ZBP 1，通过结合胞质溶胶中的外源DNA来启动先天性免疫应答。为了完全激活免疫应答，在N末端需要三个DNA结合结构域：两个Z-DNA结合结构域（ZBD），Z α和Z β，以及相邻的推定的B-DNA结合结构域。与Z-DNA复合的人DAI的Z β结构域（hZ β（DAI））的晶体结构揭示了不同于其他已知Z-DNA结合蛋白的结构特征，并且其被分类为II组ZBD。为了获得对hZ beta（DAI）的DNA结合机制的结构见解，解析了游离hZ beta（DAI）的溶液结构，并通过NMR光谱分析了其与B-和Z-DNA的结合。与Z-DNA结合的结构相比，游离hZ β（DAI）的构象在α 3识别螺旋、“翼”和Y145中具有显著的改变，这在Z-DNA识别中是关键的。与其他一些Za结构域不同，hZ beta（DAI）似乎具有构象灵活性，Z-DNA结合需要结构适应。化学位移扰动实验表明，hZ β（DAI）也通过不同的结合模式与B-DNA弱结合。据报道，DAI的C-末端结构域在B-DNA结合时发生构象变化;因此，这些变化可能是相关的。在天然免疫应答过程中，hZ β（DAI）可能在与B和Z构象的DNA结合识别外源DNA中发挥积极作用。
The DNA-dependent activator of IFN-regulatory factors (DAI), also known as DLM-1/ZBP1, initiates an innate immune response by binding to foreign DNAs in the cytosol. For full activation of the immune response, three DNA binding domains at the N terminus are required: two Z-DNA binding domains (ZBDs), Z alpha and Z beta, and an adjacent putative B-DNA binding domain. The crystal structure of the Z beta domain of human DAI (hZ beta(DAI)) in complex with Z-DNA revealed structural features distinct from other known Z-DNA binding proteins, and it was classified as a group II ZBD. To gain structural insights into the DNA binding mechanism of hZ beta(DAI), the solution structure of the free hZ beta(DAI) was solved, and its bindings to B-and Z-DNAs were analyzed by NMR spectroscopy. Compared to the Z-DNA-bound structure, the conformation of free hZ beta(DAI) has notable alterations in the alpha 3 recognition helix, the "wing," and Y145, which are critical in Z-DNA recognition. Unlike some other Za domains, hZ beta(DAI) appears to have conformational flexibility, and structural adaptation is required for Z-DNA binding. Chemical-shift perturbation experiments revealed that hZ beta(DAI) also binds weakly to B-DNA via a different binding mode. The C-terminal domain of DAI is reported to undergo a conformational change on B-DNA binding; thus, it is possible that these changes are correlated. During the innate immune response, hZ beta(DAI) is likely to play an active role in binding to DNAs in both B and Z conformations in the recognition of foreign DNAs.