Human Cytomegalovirus Major Immediate Early 1 Protein Targets Host Chromosomes by Docking to the Acidic Pocket on the Nucleosome Surface
Human Cytomegalovirus Major Immediate Early 1 Protein Targets Host Chromosomes by Docking to the Acidic Pocket on the Nucleosome Surface
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DOI：
10.1128/jvi.02606-13
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发表时间：
2014-01-01
影响因子：
5.4
通讯作者：
Nevels, Michael
中科院分区：
文献类型：
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作者：
Muecke, Katrin;Paulus, Christina;Nevels, Michael
由人巨细胞病毒（hCMV）编码的72-kDa立即早期1（IE 1）蛋白是病毒和细胞转录的核定位混杂调节剂。IE 1长期以来一直被认为与宿主有丝分裂染色质相关，但这种相互作用的机制尚未明确。在这项研究中，我们确定了IE 1的细胞染色体受体。我们证明，病毒蛋白的目标是人类核小体直接结合到核心组蛋白的核酸非依赖性的方式。IE 1具有两个可分离的组蛋白相互作用区域，对H2 A-H2 B和H3 H4具有不同的结合特异性。H2 A-H2 B结合区域被定位到IE 1的染色质束缚结构域（CTD）内进化上保守的10个氨基酸基序。结合实验方法和分子模拟的结果表明，IE 1 CTD采用β-发夹结构，与核小体表面H2 A-H2 B形成的酸性口袋对接。IE 1以与卡波西肉瘤相关疱疹病毒的潜伏相关核抗原（拉娜）相似的方式结合酸性口袋。因此，IE 1和拉娜CTD竞争结合核小体核心和染色质。我们的工作详细阐明了一个关键的病毒调节剂是如何锚定到人类染色体，并确定了核小体酸性口袋作为一个联合目标的蛋白质从远亲病毒。基于IE 1和拉娜CTD之间的惊人相似性以及IE 1靶向核小体甚至在hCMV的“临床”毒株中也不适于生产性复制的事实，我们推测这两种病毒蛋白在其各自病毒的潜伏期期间可能具有类似的功能。
The 72-kDa immediate early 1 (IE1) protein encoded by human cytomegalovirus (hCMV) is a nuclearly localized promiscuous regulator of viral and cellular transcription. IE1 has long been known to associate with host mitotic chromatin, yet the mechanisms underlying this interaction have not been specified. In this study, we identify the cellular chromosome receptor for IE1. We demonstrate that the viral protein targets human nucleosomes by directly binding to core histones in a nucleic acid-independent manner. IE1 exhibits two separable histone-interacting regions with differential binding specificities for H2A-H2B and H3H4. The H2A-H2B binding region was mapped to an evolutionarily conserved 10-amino-acid motif within the chromatin-tethering domain (CTD) of IE1. Results from experimental approaches combined with molecular modeling indicate that the IE1 CTD adopts a beta-hairpin structure, docking with the acidic pocket formed by H2A-H2B on the nucleosome surface. IE1 binds to the acidic pocket in a way similar to that of the latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus. Consequently, the IE1 and LANA CTDs compete for binding to nucleosome cores and chromatin. Our work elucidates in detail how a key viral regulator is anchored to human chromosomes and identifies the nucleosomal acidic pocket as a joint target of proteins from distantly related viruses. Based on the striking similarities between the IE1 and LANA CTDs and the fact that nucleosome targeting by IE1 is dispensable for productive replication even in "clinical" strains of hCMV, we speculate that the two viral proteins may serve analogous functions during latency of their respective viruses.