Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling
Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling
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DOI：
10.1107/s2053230x1303135x
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发表时间：
2014-01-01
影响因子：
0.9
通讯作者：
Wu, Jia-Wei
中科院分区：
文献类型：
--
作者：
Li, He;Wang, Jue;Wu, Jia-Wei
HIN-200蛋白家族在炎症相关过程中发挥重要作用。其中，AIM 2（在黑色素瘤2中不存在）和IFI 16（γ-干扰素诱导蛋白16）识别双链DNA以启动炎症反应。相比之下，p202，一种含有两个HIN结构域（HINa和HINb）的小鼠干扰素诱导蛋白，已被报道在小鼠中抑制Aim 2介导的炎症信号传导。为了理解抑制机制，确定了与20 bp DNA复合的p202 HINa结构域的晶体结构，其中p202 HINa通过静电吸引非特异性地识别DNA的两条链。p202 HINa结构域比AIM 2 HIN更紧密地结合DNA，并且p202 HINa的DNA结合模式不同于AIM 2 HIN和IFI 16 HINb结构域。这些结果，连同所报道的关于p202 HINb的数据，导致全长p202和dsDNA的相互作用模型，其为p202对Aim 2炎性小体激活的负调节提供了可能的机制。
The HIN-200 family of proteins play significant roles in inflammation-related processes. Among them, AIM2 (absent in melanoma 2) and IFI16 (gamma-interferon-inducible protein 16) recognize double-stranded DNA to initiate inflammatory responses. In contrast, p202, a mouse interferon-inducible protein containing two HIN domains (HINa and HINb), has been reported to inhibit Aim2-mediated inflammatory signalling in mouse. To understand the inhibitory mechanism, the crystal structure of the p202 HINa domain in complex with a 20 bp DNA was determined, in which p202 HINa nonspecifically recognizes both strands of DNA through electrostatic attraction. The p202 HINa domain binds DNA more tightly than does AIM2 HIN, and the DNA-binding mode of p202 HINa is different from that of the AIM2 HIN and IFI16 HINb domains. These results, together with the reported data on p202 HINb, lead to an interaction model for full-length p202 and dsDNA which provides a conceivable mechanism for the negative regulation of Aim2 inflammasome activation by p202.