Structure function studies of a molecular complex for generating viral membrane

用于生成病毒膜的分子复合物的结构功能研究

• 批准号: 10170273
• 负责人: Junpeng Deng
• 金额: $ 18.96万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170273
• 关键词: Antiviral Agents; Binding; C-terminal; Cell physiology; Cells; Cellular Membrane; Cellular Morphology; Complex; DNA Viruses; Data; Development; Ectopic Expression; Endoplasmic Reticulum; Evolution; Extravasation; Generations; Genome; Goals; Head; Hydrophobicity; Individual; Lipid Bilayers; Lipid Binding; Lipids; Liposomes; Mediating; Membrane; Modality; Molecular; N Domain; Organelles; Permeability; Phospholipids; Poxviridae; Process; Production; Proteins; Publications; Reporting; Roentgen Rays; Role; Structure; Tail; Testing; Vaccinia virus; Viral; Viral Proteins; Virion; Virus; Virus Replication; X-Ray Crystallography; alpha helix; hydrophilicity; innovation; insight; membrane assembly; membrane biogenesis; novel; obligate intracellular parasite; phosphatidylinositol 3-phosphate; phosphatidylinositol 4-phosphate; virus envelope

A fundamental step in replication of enveloped viruses is the generation of viral envelope. While most enveloped viruses obtain their envelope by budding from cellular compartments, nucleocytoplasmic large DNA viruses (NCLDVs), including poxvirus, asfarvirus and mimivirus, acquire their primary envelope through assembly of open-ended, crescent membranes derived from endoplasmic reticulum (ER). This highly unusual process of membrane biogenesis has been enigmatic for over half a century. Recent studies with vaccinia virus (VACV) have identified five viral proteins to be individually essential for this process. These so-called viral membrane assembly proteins (VMAPs) are thought to be involved in generating and/or stabilizing scission of ER membranes, but their mechanisms of action are unknown. We have made sustained contributions to the understanding of VACV membrane biogenesis process for over a decade, including the identification of VACV A6 as a VMAP and the determination of the structures of A6 and another VACV VMAP, H7. We found that H7 binds phosphatidylinositol-3-phosphate (PI3P) and phosphatidylinositol-4-phosphate (PI4P) and that A6 C- terminal domain (A6-C) traps multiple lipids with a membrane bilayer-like configuration, revealing a novel molecular modality for enclosing the lipid bilayer. Moreover, we uncovered an essential interaction between A6 and H7 by employing a novel experimental viral evolution approach. These findings led to our innovative hypothesis that H7 and A6 bind respectively to the hydrophilic head and the hydrophobic acyl tail of phospholipids, working in concert to generate and/or stabilize open-ended membrane sheets. With a long-term goal of fully elucidating the poxvirus membrane biogenesis process, our current objective is to test our novel hypothesis and determine the molecular mechanism by which A6 and H7 coordinate in membrane scission and remodeling. Aim 1. To determine the mechanism by which A6 coordinates with H7 in binding lipids. Aim 2. To determine the roles of A6 and H7 in generating membrane scissions. The proposed study on poxvirus VMAPs will not only elucidate a key viral replication step for antiviral development but also provide insights into the process of cellular membrane scission and remodeling.

复制被包膜病毒的基本步骤是生成病毒信封。虽然大多数包围的病毒通过从细胞室中芽出来，而核细胞大型DNA病毒（NCLDV），包括痘病毒，阿斯法病毒和麦米病毒，通过源自内皮菌的开放式，月亮的膜（ER）来获取其主要的膜。半个多世纪以来，这种高度不寻常的膜生物发生过程一直是神秘的。疫苗病毒（VACV）的最新研究已经确定了五种病毒蛋白对于此过程至关重要。这些所谓的病毒膜组装蛋白（VMAP）被认为与ER膜的产生和/或稳定性分解有关，但是它们的作用机理尚不清楚。我们已经为了解VAVV膜生物发生过程的理解做出了持续的贡献，其中包括将VACV A6鉴定为VMAP，并确定A6和另一个VACV VMAP H7的结构。 We found that H7 binds phosphatidylinositol-3-phosphate (PI3P) and phosphatidylinositol-4-phosphate (PI4P) and that A6 C- terminal domain (A6-C) traps multiple lipids with a membrane bilayer-like configuration, revealing a novel molecular modality for enclosing the lipid bilayer.此外，我们通过采用一种新型的实验性病毒进化方法来发现A6和H7之间的基本相互作用。这些发现导致了我们创新的假设，即H7和A6分别与磷脂的亲水性头和疏水性酰基尾巴结合，共同生成和/或稳定开放式膜片。我们的长期目标是完全阐明痘病毒膜生物发生过程，我们目前的目标是检验我们的新假设，并确定A6和H7在膜分裂和重塑中坐标的分子机制。目的1。确定A6与H7在结合脂质中坐标的机制。目标2。确定A6和H7在产生膜剪裁中的作用。拟议的有关痘病毒VMAP的研究不仅将阐明抗病毒发育的关键病毒复制步骤，而且还提供了有关细胞膜分裂和重塑过程的见解。

项目成果

Human SAMD9 is a poxvirus-activatable anticodon nuclease inhibiting codon-specific protein synthesis.

• DOI: 10.1126/sciadv.adh8502
• 发表时间: 2023-06-09
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Zhang, Fushun;Ji, Quanquan;Chaturvedi, Juhi;Morales, Marisol;Mao, Yuanhui;Meng, Xiangzhi;Dong, Leiming;Deng, Junpeng;Qian, Shu-Bing;Xiang, Yan
• 通讯作者: Xiang, Yan

Monkeypox virus emerges from the shadow of its more infamous cousin: family biology matters.

• DOI: 10.1080/22221751.2022.2095309
• 发表时间: 2022-12
• 期刊: Emerging microbes & infections
• 影响因子: 13.2

Structure of the unique tetrameric STENOFOLIA homeodomain bound with target promoter DNA.

• DOI: 10.1107/s205979832100632x
• 发表时间: 2021-08-01
• 期刊: Acta crystallographica. Section D, Structural biology
• 作者: Pathak PK;Zhang F;Peng S;Niu L;Chaturvedi J;Elliott J;Xiang Y;Tadege M;Deng J
• 通讯作者: Deng J