CRYSTAL STRUCTURE OF THE KSHV PROCESSIVITY FACTOR, PF-8

KSHV 连续性因子 PF-8 的晶体结构

• 批准号: 7955142
• 负责人: JAMES HOGLE
• 金额: $ 2.2万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955142
• 关键词: Binding; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; DNA; DNA Sequence Rearrangement; DNA biosynthesis; DNA-Directed DNA Polymerase; Data; Funding; Grant; Head; Herpesviridae; Herpesvirus 1; Human; Human Herpesvirus 8; Institution; Kaposi Sarcoma; Lymphoma; Lymphoproliferative Disorders; Modeling; Multicentric Angiofollicular Lymphoid Hyperplasia; Polymerase; Proliferating Cell Nuclear Antigen; Research; Research Personnel; Resources; Site; Source; Structure; United States National Institutes of Health; Viral; base; comparative; dimer; effusion; falls; gammaherpesvirus; insight; monomer; sarcoma; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human herpesvirus-8 (HHV-8), also known as Karposi's sarcoma-associated human herpesvirus (KSHV), is a gammaherpesvirus that is the causative agent of various lymphoproliferative disorders including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV encodes the viral processivity factor, PF-8, which binds to DNA and is essential for maintaining contact between the viral polymerase Pol-8 and DNA during DNA synthesis. The crystal structures of a processivity factor from the alpha herpesvirus, HSV-1, and the beta herpesvirus, HCMV, revealed structures similar to that of the eukaryotic processivity factor, proliferating cell nuclear antigen (PCNA), except in their quaternary rearrangement. PCNA forms a trimeric ring around DNA while the processivity factors from HSV-1 and HCMV are a monomer and dimer respectively and do not require a clamp loader or ATP in order to be loaded onto DNA. We have determined the crystal structure of PF-8 to 2.8¿, and show that PF-8 forms a head-to-head homodimer that appears to fall, functionally, somewhere between the structures of UL42 and UL44. Based on the structural data, we are able to identify possible sites for interactions with DNA and polymerase, to propose a model for the simultaneous interaction of all three components of the complex. In addition, the availability of crystal structures for all three herpesvirus classes provides new insights into comparative structure and function.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 人类疱疹病毒 8 (HHV-8) 也称为卡波西肉瘤相关人类疱疹病毒 (KSHV)，是一种伽马疱疹病毒，是多种淋巴组织增生性疾病的病原体，包括卡波西肉瘤、原发性渗出性淋巴瘤和多中心卡斯尔曼病。 KSHV 编码病毒持续生长因子 PF-8，该因子与 DNA 结合，对于在 DNA 合成过程中维持病毒聚合酶 Pol-8 和 DNA 之间的接触至关重要。来自α疱疹病毒HSV-1和β疱疹病毒HCMV的持续生长因子的晶体结构揭示了与真核持续生长因子增殖细胞核抗原（PCNA）相似的结构，除了它们的四级重排之外。 PCNA 在 DNA 周围形成三聚环，而来自 HSV-1 和 HCMV 的持续合成因子分别是单体和二聚体，不需要夹具加载器或 ATP 即可加载到 DNA 上。 我们已经确定了 PF-8 的晶体结构为 2.8¿，并表明 PF-8 形成了头对头的同二聚体，其功能似乎介于 UL42 和 UL44 的结构之间。根据结构数据，我们能够识别与 DNA 和聚合酶相互作用的可能位点，从而提出复合物所有三个组分同时相互作用的模型。此外，所有三种疱疹病毒类别的晶体结构的可用性为比较结构和功能提供了新的见解。