Crystal Structure of the DNA-Binding Domain of Human Herpesvirus 6A Immediate Early Protein 2
Crystal Structure of the DNA-Binding Domain of Human Herpesvirus 6A Immediate Early Protein 2
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人疱疹病毒 6A 立即早期蛋白 2 DNA 结合域的晶体结构
DOI：
10.1128/jvi.01121-17
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发表时间：
2017
影响因子：
5.4
通讯作者：
Mori Yasuko
中科院分区：
文献类型：
--
作者：
Nishimura Mitsuhiro;Wang Junjie;Wakata Aika;Sakamoto Kento;Mori Yasuko
人类疱疹病毒6A(HHV-6A)的即刻早期蛋白在裂解感染开始时表达，从而调节病毒基因的表达。HHV-6A的即刻早期蛋白2(IE2)是一种反式激活因子，可驱动多种启动子。HHV-6A IE2的C末端区域在贝塔疱疹病毒的IE2同源物中是共有的，参与二聚化、DNA结合和转录因子结合。在本研究中，通过X射线结晶学在2.5Å的分辨率下确定了IE2的C-末端结构域(IE2-CTD)。同源二聚体由具有两个互换的长环的β桶核稳定。出人意料的是，其核心结构类似于Epstein-Barr病毒的伽马疱疹病毒因子EBNA1和卡波西肉瘤相关疱疹病毒的LANA，但IE2-CTD中的互换环更长，并在其末端形成螺旋-转角-螺旋(HTH)样基序。HTH和周围的α-螺旋形成IE2组特有的结构特征。表观DNA结合位点(基于与EBNA1和LANA的结构相似性)位于HTH类基序的相反一侧，周围有正静电势。对三维结构上保守残基的图谱分析显示，在预期的DNA结合位点附近有一个潜在的因子结合位点。预测的两个或三个功能位点表明IE2-CTD作为连接启动子和驱动基因表达的转录因子的适配器。人类疱疹病毒6A(HHV-6A)和HHV-6B属于β疱疹病毒亚家族。这两种病毒在初次感染后都会建立终生潜伏期，它们的重新激活对免疫受损的患者构成了重大风险。HHV-6A和HHV-6B的即刻早期蛋白2(IE2)是一种反式激活因子，其DNA结合域与人类疱疹病毒7型和人巨细胞病毒等其他β疱疹病毒相似。在本研究中，我们测定和分析了HHV-6A IE2的DNA结合域的原子结构，从而能够基于结构了解IE2的功能，特别是DNA识别和与转录因子的相互作用。出人意料的是，二聚体核心类似于伽马疱疹病毒转录调节因子的DNA结合域，表现出作为DNA结合域的结构保守性，但有自己独特的结构特征。这些发现有助于进一步描述这一关键的病毒反式激活因子。
Immediate early proteins of human herpesvirus 6A (HHV-6A) are expressed at the outset of lytic infection and thereby regulate viral gene expression. Immediate early protein 2 (IE2) of HHV-6A is a transactivator that drives a variety of promoters. The C-terminal region of HHV-6A IE2 is shared among IE2 homologs in betaherpesviruses and is involved in dimerization, DNA binding, and transcription factor binding. In this study, the structure of the IE2 C-terminal domain (IE2-CTD) was determined by X-ray crystallography at a resolution of 2.5 Å. IE2-CTD forms a homodimer stabilized by a β-barrel core with two interchanging long loops. Unexpectedly, the core structure resembles those of the gammaherpesvirus factors EBNA1 of Epstein-Barr virus and LANA of Kaposi sarcoma-associated herpesvirus, but the interchanging loops are longer in IE2-CTD and form helix-turn-helix (HTH)-like motifs at their tips. The HTH and surrounding α-helices form a structural feature specific to the IE2 group. The apparent DNA-binding site (based on structural similarity with EBNA1 and LANA) resides on the opposite side of the HTH-like motifs, surrounded by positive electrostatic potential. Mapping analysis of conserved residues on the three-dimensional structure delineated a potential factor-binding site adjacent to the expected DNA-binding site. The predicted bi- or tripartite functional sites indicate a role for IE2-CTD as an adapter connecting the promoter and transcriptional factors that drive gene expression.IMPORTANCEHuman herpesvirus 6A (HHV-6A) and HHV-6B belong to betaherpesvirus subfamily. Both viruses establish lifelong latency after primary infection, and their reactivation poses a significant risk to immunocompromised patients. Immediate early protein 2 (IE2) of HHV-6A and HHV-6B is a transactivator that triggers viral replication and contains a DNA-binding domain shared with other betaherpesviruses such as human herpesvirus 7 and human cytomegalovirus. In this study, an atomic structure of the DNA-binding domain of HHV-6A IE2 was determined and analyzed, enabling a structure-based understanding of the functions of IE2, specifically DNA recognition and interaction with transcription factors. Unexpectedly, the dimeric core resembles the DNA-binding domain of transcription regulators from gammaherpesviruses, showing structural conservation as a DNA-binding domain but with its own unique structural features. These findings facilitate further characterization of this key viral transactivator.
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DOI：
10.1093/infdis/162.4.852
发表时间：
1990
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
Huamin Tang;Y. Mori
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