Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly

• Published in: PLoS pathogens Vol. 11; no. 12; p. e1005322
• Main Authors: Xu, Kai, Chan, Yee-Peng, Bradel-Tretheway, Birgit, Akyol-Ataman, Zeynep, Zhu, Yongqun, Dutta, Somnath, Yan, Lianying, Feng, YanRu, Wang, Lin-Fa, Skiniotis, Georgios, Lee, Benhur, Zhou, Z. Hong, Broder, Christopher C., Aguilar, Hector C., Nikolov, Dimitar B.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2015; Public Library of Science (PLoS)
• Subjects: BASIC BIOLOGICAL SCIENCES; Cell fusion; Crystal structure; Crystallography, X-Ray; Crystals; Data collection; Electrophoresis, Polyacrylamide Gel; Flow cytometry; Fusion; Glycoproteins; HEK293 Cells; Henipavirus Infections - metabolism; Host cells; Humans; Influenza; Membrane fusion; Mutagenesis, Site-Directed; Nipah virus; Nipah Virus - chemistry; Nipah Virus - metabolism; Oligomers; Protein Conformation; Proteins; Structure; Tomography; Viral entry; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; Virus glycoproteins; Virus Internalization; Virus research; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005322

Nipah virus (NiV) is a paramyxovirus that infects host cells through the coordinated efforts of two envelope glycoproteins. The G glycoprotein attaches to cell receptors, triggering the fusion (F) glycoprotein to execute membrane fusion. Here we report the first crystal structure of the pre-fusion form of the NiV-F glycoprotein ectodomain. Interestingly this structure also revealed a hexamer-of-trimers encircling a central axis. Electron tomography of Nipah virus-like particles supported the hexameric pre-fusion model, and biochemical analyses supported the hexamer-of-trimers F assembly in solution. Importantly, structure-assisted site-directed mutagenesis of the interfaces between F trimers highlighted the functional relevance of the hexameric assembly. Shown here, in both cell-cell fusion and virus-cell fusion systems, our results suggested that this hexamer-of-trimers assembly was important during fusion pore formation. We propose that this assembly would stabilize the pre-fusion F conformation prior to cell attachment and facilitate the coordinated transition to a post-fusion conformation of all six F trimers upon triggering of a single trimer. Together, our data reveal a novel and functional pre-fusion architecture of a paramyxoviral fusion glycoprotein.