Structural Studies of Paramyxovirus fusion proteins

描述（由申请方提供）：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附着蛋白HN、H或G（取决于病毒）和融合（F）糖蛋白。在本提案中将研究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一个蛋白水解活化步骤，使受体结合，受体破坏和融合促进活动。该提案还将重点研究F糖蛋白，以深入了解副粘病毒家族融合前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蛋白功能。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，其成员是导致人类发病率和死亡率的重要原因。副粘病毒进入细胞需要病毒和细胞脂膜的融合。该过程通过病毒融合糖蛋白（F）进行，通常在其被与宿主细胞受体结合的病毒附着蛋白（HN、H或G）激活后进行。这项研究计划的重点是进一步了解F和HN蛋白，以及它们在病毒进入和感染中如何交流和发挥作用。此外，拟议的研究将调查针对F蛋白的抗体如何中和病毒。本研究结果对开发新型抗病毒药物和疫苗具有重要意义。

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.