Structures of Langya Virus Fusion Protein Ectodomain in Pre- and Postfusion Conformation.
Structures of Langya Virus Fusion Protein Ectodomain in Pre- and Postfusion Conformation.
复制标题
狼牙病毒融合蛋白胞外域融合前和融合后构象的结构。
DOI：
10.1128/jvi.00433-23
复制
发表时间：
2023
影响因子：
5.4
通讯作者：
Acharya,Priyamvada
中科院分区：
文献类型：
--
作者：
May,AaronJ;Pothula,KarunakarReddy;Janowska,Katarzyna;Acharya,Priyamvada
琅琊病毒（LayV）是亨尼帕病毒属的一种副粘病毒，与致命的尼帕病毒（NiV）和亨德拉病毒（HeV）密切相关，于2022年8月在中国东部动物暴露后通过疾病监测发现。副粘病毒在其表面上呈现两种糖蛋白，称为附着蛋白和融合蛋白，其介导进入细胞并构成免疫应答的主要抗原靶标。在这里，我们确定冷冻电子显微镜（cryo-EM）结构的未切割的LayV融合蛋白（F）胞外域在融合前和融合后的构象。LayV-F蛋白表现出融合前和融合后的结构，尽管在副粘病毒中高度保守，但在其表面性质上显示出差异，特别是在融合前三聚体的顶点，这可能有助于抗原变异性。虽然在融合前和融合后的LayV-F蛋白质之间观察到了巨大的构象变化，但几个结构域保持不变，通过高度保守的二硫化物保持在一起。LayV-F融合肽（FP）在融合前状态下被埋在高度保守的疏水性蛋白质间口袋中，并且明显比蛋白质的其余部分灵活性低，突出了其“弹簧加载”状态，并表明前-后过渡的机制必须涉及口袋的扰动和融合肽的释放。总之，这些结果提供了一个结构基础如何琅琊病毒融合蛋白相比，其亨尼帕病毒的亲戚，并提出了一个机制的前融合后转换的初始步骤，可能适用于更广泛的副粘virus.IMPORTANCETheHenipavirusgenus迅速扩大到新的动物宿主和地理位置。本研究比较了琅琊病毒融合蛋白的结构和抗原性，其他亨尼帕病毒，这具有重要的疫苗和治疗发展的意义。此外，该研究提出了一种新的机制来解释融合起始过程的早期步骤，可以更广泛地应用于副粘病毒科。
Langya virus (LayV) is a paramyxovirus in theHenipavirusgenus, closely related to the deadly Nipah (NiV) and Hendra (HeV) viruses, that was identified in August 2022 through disease surveillance following animal exposure in eastern China. Paramyxoviruses present two glycoproteins on their surface, known as attachment and fusion proteins, that mediate entry into cells and constitute the primary antigenic targets for immune response. Here, we determine cryo-electron microscopy (cryo-EM) structures of the uncleaved LayV fusion protein (F) ectodomain in pre- and postfusion conformations. The LayV-F protein exhibits pre- and postfusion architectures that, despite being highly conserved across paramyxoviruses, show differences in their surface properties, in particular at the apex of the prefusion trimer, that may contribute to antigenic variability. While dramatic conformational changes were visualized between the pre- and postfusion forms of the LayV-F protein, several domains remained invariant, held together by highly conserved disulfides. The LayV-F fusion peptide (FP) is buried within a highly conserved, hydrophobic interprotomer pocket in the prefusion state and is notably less flexible than the rest of the protein, highlighting its “spring-loaded” state and suggesting that the mechanism of pre-to-post transition must involve perturbations to the pocket and release of the fusion peptide. Together, these results offer a structural basis for how the Langya virus fusion protein compares to its Henipavirus relatives and propose a mechanism for the initial step of pre- to postfusion conversion that may apply more broadly to paramyxoviruses.IMPORTANCETheHenipavirusgenus is quickly expanding into new animal hosts and geographic locations. This study compares the structure and antigenicity of the Langya virus fusion protein to other henipaviruses, which have important vaccine and therapeutic development implications. Furthermore, the study proposes a new mechanism to explain the early steps of the fusion initiation process that can be more broadly applied to theParamyxoviridaefamily.