Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
Laboratory of Structural Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Int J Biol Macromol. 2023 Aug 1;245:125461. doi: 10.1016/j.ijbiomac.2023.125461. Epub 2023 Jun 20.
The hematopoietic interferon-inducible nuclear (HIN) domain of the PYHIN family of proteins recognizes double-stranded DNA (dsDNA) through different dsDNA-binding modes. These modes apparently confer different roles upon these proteins in the regulation of innate immune responses, gene transcription, and apoptosis. Myeloid cell nuclear differentiation antigen (MNDA), a member of the human PYHIN family, binds DNA and regulates gene transcription in monocytes. However, the mechanism of DNA recognition and DNA-binding modes of human MNDA (hMNDA) remain unclear. Here, we determined the crystal structure of the hMNDA-HIN domain in complex with dsDNA at 2.4 Å resolution, and reveal that hMNDA-HIN binds to dsDNA in a sequence-independent manner. Structure and mutation studies indicated that hMNDA-HIN binds to dsDNA through a unique mode, involving two dsDNA-binding interfaces. Interface I exhibits an AIM2-like dsDNA-binding mode, and interface II has a previously unreported mode of dsDNA-binding. These results provide new insights into the DNA-binding modes of this PYHIN protein.
PYHIN 家族蛋白的造血干扰素诱导核（HIN）结构域通过不同的双链 DNA（dsDNA）结合模式识别双链 DNA（dsDNA）。这些模式显然赋予了这些蛋白在调节先天免疫反应、基因转录和细胞凋亡方面的不同作用。人 PYHIN 家族的髓系细胞核分化抗原（MNDA）与 DNA 结合并调节单核细胞中的基因转录。然而，人 MNDA（hMNDA）的 DNA 识别机制和 DNA 结合模式仍不清楚。在这里，我们以 2.4 Å 的分辨率确定了 hMNDA-HIN 结构域与 dsDNA 复合物的晶体结构，并揭示 hMNDA-HIN 以序列非依赖性方式结合 dsDNA。结构和突变研究表明，hMNDA-HIN 通过一种独特的模式与 dsDNA 结合，涉及两个 dsDNA 结合界面。界面 I 表现出类似于 AIM2 的 dsDNA 结合模式，界面 II 具有以前未报道的 dsDNA 结合模式。这些结果为该 PYHIN 蛋白的 DNA 结合模式提供了新的见解。
