The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly.
The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly.
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人巨细胞病毒终止酶亚基 pUL51 的 C 端部分是终止酶复合物组装的中心
DOI：
10.1099/jgv.0.000984
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Borst EM
中科院分区：
文献类型：
--
作者：
Neuber S;Wagner K;Messerle M;Borst EM
人类巨细胞病毒 (HCMV) 基因组的切割和包装是通过病毒终止酶完成的，包括 pUL56 和 pUL89 以及最近鉴定的 pUL51 亚基。由于有关 pUL51 的知识很少，我们的目标是识别对终止酶组装很重要的 pUL51 结构域。计算机模拟分析表明，pUL51 的 N 端部分本质上是无序的，并且 α 螺旋存在于 C 端部分。在病毒基因组背景下对 pUL51 进行接头扫描诱变揭示，预测的 α 螺旋中的氨基酸插入与病毒生长不相容，而在对假定的无序部分进行诱变后，与 pUL56 和 pUL89 的相互作用得以保留，并产生了病毒后代。用小鼠巨细胞病毒密切相关的 M51 蛋白替换 pUL51 并没有产生活病毒，表明 M51 不能替代 pUL51，并且交换 M51 和 UL51 N 端和 C 端证明了 pUL51 C 端部分在构建终止酶复合物中的关键作用。值得注意的是，事实证明，仅 pUL51 C 末端就足以实现终止酶组装、其核定位和噬菌斑形成。使用表达不同标记的 pUL51 版本的 HCMV 突变体，我们没有检测到 pUL51 的寡聚化，正如针对其他疱疹病毒的 pUL51 直系同源物所提出的那样。这些数据提供了对 pUL51 与其他两种终止酶成分相互作用的深入了解，并为阐明针对 HCMV 终止酶的新型抗病毒药物的作用模式提供了基础。
The cleavage and packaging of the human cytomegalovirus (HCMV) genome is accomplished by the viral terminase, comprising pUL56 and pUL89, and the recently identified pUL51 subunit. Since knowledge about pUL51 is scarce, we aimed at identifying pUL51 domains that are important for terminase assembly.In silicoanalysis suggested that the N-terminal half of pUL51 is intrinsically disordered, and that α-helices are present in the C-terminal part. Linker-scanning mutagenesis of pUL51 in the context of the viral genome revealed that amino acid insertions into the predicted α-helices are not compatible with viral growth, whereas upon mutagenesis of the putatively disordered parts interaction with pUL56 and pUL89 was retained and viral progeny was produced. Replacement of pUL51 with the closely related M51 protein of mouse cytomegalovirus did not lead to viable virus, indicating that M51 cannot substitute for pUL51, and swapping the M51 and UL51 N- and C-termini demonstrated the critical role of the pUL51 C-terminal part in building the terminase complex. Notably, the pUL51 C-terminus alone turned out to be sufficient to enable terminase assembly, its nuclear localization and plaque formation. Using HCMV mutants expressing differently tagged pUL51 versions, we did not detect oligomerization of pUL51, as has been proposed for the pUL51 orthologues of other herpesviruses. These data provide an insight into the interaction of pUL51 with the other two terminase components, and provide the basis for unravelling the mode of action of novel antiviral drugs targeting the HCMV terminase.
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