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首页> 美国卫生研究院文献>PLoS Pathogens >Atomic structures and deletion mutant reveal different capsid-binding patterns and functional significance of tegument protein pp150 in murine and human cytomegaloviruses with implications for therapeutic development
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Atomic structures and deletion mutant reveal different capsid-binding patterns and functional significance of tegument protein pp150 in murine and human cytomegaloviruses with implications for therapeutic development

机译：原子结构和缺失突变体揭示了鼠和人巨细胞病毒中外皮蛋白pp150的不同衣壳结合模式和功能意义对治疗发展具有重要意义

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Cytomegalovirus (CMV) infection causes birth defects and life-threatening complications in immunosuppressed patients. Lack of vaccine and need for more effective drugs have driven widespread ongoing therapeutic development efforts against human CMV (HCMV), mostly using murine CMV (MCMV) as the model system for preclinical animal tests. The recent publication (Yu et al., 2017, DOI: ) of an atomic model for HCMV capsid with associated tegument protein pp150 has infused impetus for rational design of novel vaccines and drugs, but the absence of high-resolution structural data on MCMV remains a significant knowledge gap in such development efforts. Here, by cryoEM with sub-particle reconstruction method, we have obtained the first atomic structure of MCMV capsid with associated pp150. Surprisingly, the capsid-binding patterns of pp150 differ between HCMV and MCMV despite their highly similar capsid structures. In MCMV, pp150 is absent on triplex Tc and exists as a “Λ”-shaped dimer on other triplexes, leading to only 260 groups of two pp150 subunits per capsid in contrast to 320 groups of three pp150 subunits each in a “Δ”-shaped fortifying configuration. Many more amino acids contribute to pp150-pp150 interactions in MCMV than in HCMV, making MCMV pp150 dimer inflexible thus incompatible to instigate triplex Tc-binding as observed in HCMV. While pp150 is essential in HCMV, our pp150-deletion mutant of MCMV remained viable though with attenuated infectivity and exhibiting defects in retaining viral genome. These results thus invalidate targeting pp150, but lend support to targeting capsid proteins, when using MCMV as a model for HCMV pathogenesis and therapeutic studies.
机译：巨细胞病毒（CMV）感染会导致免疫抑制患者先天缺陷和危及生命的并发症。疫苗的缺乏和对更有效药物的需求推动了针对人类CMV（HCMV）的广泛正在进行的治疗开发努力，其中大部分是将鼠CMV（MCMV）用作临床前动物测试的模型系统。 HCMV衣壳与相关外皮蛋白pp150的原子模型的最新出版物（Yu等，2017，DOI：）为新型疫苗和药物的合理设计注入了动力，但仍缺乏MCMV的高分辨率结构数据在此类开发工作中存在巨大的知识差距。在这里，通过带有子粒子重构方法的cryoEM，我们获得了带有pp150的MCMV衣壳的第一个原子结构。令人惊讶地，尽管HCMV和MCMV的衣壳结构高度相似，但是pp150的衣壳结合模式不同。在MCMV中，三元组Tc上不存在pp150，而在其他三元组上以“Λ”形二聚体存在，导致每个衣壳中只有260组两个pp150亚基，而每个“衣壳”中则有320组三个pp150亚基。形状的强化配置。与HCMV中相比，在MCMV中更多的氨基酸对pp150-pp150的相互作用有贡献，从而使MCMV pp150二聚体变得不灵活，因此与在HCMV中观察到的三链Tc结合不相容。尽管pp150在HCMV中是必不可少的，但我们的mcMV的pp150缺失突变体虽然感染力减弱，但在保留病毒基因组方面表现出缺陷，但仍保持活力。因此，当使用MCMV作为HCMV发病机理和治疗研究的模型时，这些结果会使靶向pp150无效，但有助于靶向衣壳蛋白。

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