HSV-1 ICP0 Dimer Domain Adopts a Novel β-barrel Fold.
HSV-1 ICP0 Dimer Domain Adopts a Novel β-barrel Fold.
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HSV-1 ICP0 二聚体结构域采用新型 β 桶折叠。
DOI：
10.1101/2024.01.16.575752
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Davido,DavidJ
中科院分区：
文献类型：
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作者：
McCloskey,Erick;Kashipathy,Maithri;Cooper,Anne;Gao,Philip;Johnson,DavidK;Battaile,KevinP;Lovell,Scott;Davido,DavidJ
感染细胞蛋白0（ICP 0）是一种具有E3泛素连接酶活性的单纯疱疹病毒1型（HSV-1）的立即早期调节蛋白。ICP 0部分通过其C末端二聚体结构域（残基555-767）反式激活病毒基因。该二聚体结构域的缺失导致病毒基因表达降低、裂解性感染和从潜伏期再激活。由于ICP 0的二聚体结构域与其反式激活活性和有效的病毒复制有关，因此我们希望确定该特定结构域的结构。从细菌中纯化ICP 0的C末端，并通过X射线晶体学分析以解析其结构。ICP 0二聚体中的每个亚基或单体由9条β链和2条α螺旋组成。有趣的是，在二聚体形成过程中，来自一个单体的两个相邻的β链“到达”相邻的亚基，产生两个β桶状结构。此外，晶体学分析表明四聚体结构由每个二聚体的两个β链形成，产生β桶的“堆叠”。结构蛋白数据库检索表明ICP 0二聚体采用的折叠或结构是新的。二聚体通过广泛的氢键网络结合在一起。计算分析表明，ICP 0可以形成二聚体或通过其C末端SUMO相互作用基序与SUMO 1结合，但不能两者兼而有之。了解二聚体结构域的结构将有助于深入了解ICP 0的活性，并最终了解HSV-1的生命周期。
Infected cell protein 0 (ICP0) is an immediate‐early regulatory protein of herpes simplex virus 1 (HSV‐1) that possesses E3 ubiquitin ligase activity. ICP0 transactivates viral genes, in part, through its C‐terminal dimer domain (residues 555–767). Deletion of this dimer domain results in reduced viral gene expression, lytic infection, and reactivation from latency. Since ICP0's dimer domain is associated with its transactivation activity and efficient viral replication, we wanted to determine the structure of this specific domain. The C‐terminus of ICP0 was purified from bacteria and analyzed by X‐ray crystallography to solve its structure. Each subunit or monomer in the ICP0 dimer is composed of nine β‐strands and two α‐helices. Interestingly, two adjacent β‐strands from one monomer “reach” into the adjacent subunit during dimer formation, generating two β‐barrel‐like structures. Additionally, crystallographic analyses indicate a tetramer structure is formed from two β‐strands of each dimer, creating a “stacking” of the β‐barrels. The structural protein database searches indicate the fold or structure adopted by the ICP0 dimer is novel. The dimer is held together by an extensive network of hydrogen bonds. Computational analyses reveal that ICP0 can either form a dimer or bind to SUMO1 via its C‐terminal SUMO‐interacting motifs but not both. Understanding the structure of the dimer domain will provide insights into the activities of ICP0 and, ultimately, the HSV‐1 life cycle.