Glycoprotein interactions in paramyxovirus fusion

副粘病毒科是有包膜的负链RNA病毒，包括麻疹病毒、人类疱疹病毒和人类疱疹病毒。 副流感病毒（hPIV）1-4型、呼吸道合胞病毒、腮腺炎病毒、纽卡斯尔病病毒 (NDV)仙台病毒、猴副流感病毒5型以及新出现的亨德拉病毒和尼帕病毒。 麻疹仍然是世界范围内儿童的主要杀手， 在工业化国家，沿着腮腺炎和尼帕病毒，引起严重的CMS疾病。HPIV类型 1-3长期以来被认为是哮吼的病原体和重要的呼吸道病原体， 尤其是婴儿和儿童，hPIVS是肺炎和支气管炎的主要原因。最近，NDV 由于其选择性杀死肿瘤细胞的能力而获得重要性，并且具有用作 用于表达来自其他病毒包括流感病毒的外源基因的溶瘤剂和疫苗载体 病毒该项目的长期目标是表征 副粘病毒糖蛋白及其与靶细胞的早期相互作用。细胞病变的标志之一 副粘病毒感染细胞的作用是形成多核合胞体。这个过程是 通过两个病毒表面之间的病毒特异性相互作用诱导的膜融合介导 糖蛋白、附着（HN/H）和融合（F）蛋白。这项建议的目的是 了解副粘病毒糖蛋白之间病毒特异性相互作用的机制 在适当的时间和地点调节融合蛋白的活化。清醒的认识 这一过程将指导旨在控制这些病毒的抗病毒策略，如小分子抑制剂 通过干扰感染的早期步骤。本提案的具体目的是阐明 HN-受体相互作用的强度和HN-R水平之间相关性的分子基础 膜融合，通过融合过程跟踪糖蛋白复合物的状态，检测各种 模型提出的机制HN-F介导的融合，并证明互补性， NDV HN和F蛋白上的相互作用结构域。

The Paramyxoviridae are enveloped, negative-stranded RNA viruses, including measles virus, human parainfluenza virus (hPIV) types 1-4, respiratory syncytial virus, mumps virus, Newcastle disease virus (NDV), Sendai virus, simian parainfluenza virus 5, and the newly-emerged hendra and nipah viruses. Measles remains a major killer of children worldwide, despite successful vaccination programs in industrialized countries and .along with mumps and nipah viruses, causes severe CMSdisease. HPIV types 1-3 have long been recognized as causative agents of croup and as important respiratory pathogens, especially of infants and children and hPIVS is a major cause of pneumonia and bronchitis. Recently, NDV has gained importance for its ability to selectively kill tumor cells and has potential for use as both an oncolytic agent and a vaccine vector for expression of foreign genes from other viruses, including influenza virus. The long-term objective of this project is the characterization of the structure/function of the paramyxovirus glycoproteins and their early interactions with the target cell. One of the hallmark cytopathic effects of cells infected with paramyxoviruses is the formation of multi-nucleate syncytia. This process is mediated by membrane fusion induced by a virus-specific interaction between the two viral surface glycoproteins, the attachment (HN/H) and the fusion (F) proteins. The objective of this proposal is to understand the mechanism by which the virus-specific interaction between paramyxovirus glycoproteins regulates the activation of the fusion protein at the proper time and place. A clear understanding of this process will guide anti-viral strategies, such as small molecule inhibitors, aimed at controlling these viruses through interference with the early steps in infection. The specific aims of this proposal are to elucidate the molecular basis for the correlation between the strength of the HN-receptor interaction and the level of membrane fusion, to follow the status of the glycoprotein complex through the fusion process, to test various models proposed for the mechanism of HN-F mediated fusion and, to demonstrate the complementarity of the interacting domains on the NDV HN and F proteins.