Structural Studies of Paramyxovirus fusion proteins

描述(申请人提供)：副粘病毒感染人类和动物宿主，并导致重大人类疾病，以及具有重大经济后果的动物感染。大多数副粘病毒进入细胞需要一个附着蛋白，HN，H或G，视病毒而定，以及一个融合(F)糖蛋白。在这项建议中，将研究HN蛋白的结构和功能，以更好地了解其茎区如何控制F蛋白激活的特异性，从而触发膜融合。我们将确定为什么HN蛋白的一个子集需要蛋白水解性激活步骤来实现受体结合、受体破坏和融合促进活性。这项建议还将侧重于对F糖蛋白的研究，以深入了解副粘病毒家族中灌流构象的潜在结构差异，并更好地了解中和抗体如何参与和抑制F蛋白的功能。这项拟议的研究将为这些副粘病毒进入糖蛋白如何介导感染提供重要的新见解，并可能为抗病毒治疗的发展提供新的途径。 公共卫生相关性：副粘病毒是一个大的病毒家族，其成员是导致人类重大发病率和死亡率的原因。副粘病毒进入细胞需要病毒和细胞脂膜的融合。这一过程是由病毒融合糖蛋白(F)进行的，通常在病毒附着蛋白(HN、H或G)激活后，病毒附着蛋白与宿主细胞受体结合。这项研究计划侧重于加深我们对F蛋白和HN蛋白的理解，以及这些蛋白在病毒进入和感染过程中如何沟通和发挥作用。此外，这项拟议的研究将调查针对F蛋白的抗体是如何中和病毒的。本研究结果将对开发新型抗病毒药物和疫苗具有潜在的意义。

DESCRIPTION (provided by applicant): The Paramyxoviruses infect human and animal hosts and are responsible for causing major human illnesses, as well as animal infections of significant economic consequence. The entry into cells of most Paramyxoviruses requires an attachment protein, HN, H or G, depending on the virus, and a fusion (F) glycoprotein. In this proposal will study the structure and function of the HN protein to better understand how its stalk region controls the specificity of F protein activation, thereby triggering membrane fusion. We will determine why a subset of HN proteins require a proteolytic activation step to enable receptor binding, receptor destroying and fusion promoting activities. This proposal will also focus on the study of the F glycoproteins, to gain insight into potential structural differences in the prefusion conformations across the paramyxovirus family and to better understand how neutralizing antibodies engage and inhibit F protein functions. The proposed research will provide significant new insights into how these paramyxovirus entry glycoproteins mediate infection and potentially provide new avenues for the development of antiviral therapeutics. PUBLIC HEALTH RELEVANCE: The Paramyxoviruses are a large virus family whose members are the cause of significant human morbidity and mortality. The entry of paramyxoviruses into a cell requires the fusion of viral and cellular lipid membranes. This process is carried out by the viral fusion glycoprotein (F), typically after it is activated by a viral attachment protein (HN, H or G), which binds to a host cell receptor. This research proposal focuses on furthering our understanding of both F and HN proteins and how these communicate and function in viral entry and infection. In addition, the proposed research will investigate how antibodies directed against the F protein neutralize the virus. The results of this research will have potential significance in developing novel antiviral therapeutics and vaccines.