title: Nipah virus attachment glycoprotein stalk C-terminal region links receptor binding to fusion triggering.
abstract: Membrane fusion is essential for paramyxovirus entry into target cells and for the cell-cell fusion (syncytia) that results from many paramyxoviral infections. The concerted efforts of two membrane-integral viral proteins, the attachment (HN, H, or G) and fusion (F) glycoproteins, mediate membrane fusion. The emergent Nipah virus (NiV) is a highly pathogenic and deadly zoonotic paramyxovirus. We recently reported that upon cell receptor ephrinB2 or ephrinB3 binding, at least two conformational changes occur in the NiV-G head, followed by one in the NiV-G stalk, that subsequently result in F triggering and F execution of membrane fusion. However, the domains and residues in NiV-G that trigger F and the specific events that link receptor binding to F triggering are unknown. In the present study, we identified a NiV-G stalk C-terminal region (amino acids 159 to 163) that is important for multiple G functions, including G tetramerization, conformational integrity, G-F interactions, receptor-induced conformational changes in G, and F triggering. On the basis of these results, we propose that this NiV-G region serves as an important structural and functional linker between the NiV-G head and the rest of the stalk and is critical in propagating the F-triggering signal via specific conformational changes that open a concealed F-triggering domain(s) in the G stalk. These findings broaden our understanding of the mechanism(s) of receptor-induced paramyxovirus F triggering during viral entry and cell-cell fusion.
  
  
  OBJECTIVE
  The emergent deadly viruses Nipah virus (NiV) and Hendra virus belong to the Henipavirus genus in the Paramyxoviridae family. NiV infections target endothelial cells and neurons and, in humans, result in 40 to 75% mortality rates. The broad tropism of the henipaviruses and the unavailability of therapeutics threaten the health of humans and livestock. Viral entry into host cells is the first step of henipavirus infections, which ultimately cause syncytium formation. After attaching to the host cell receptor, henipaviruses enter the target cell via direct viral-cell membrane fusion mediated by two membrane glycoproteins: the attachment protein (G) and the fusion protein (F). In this study, we identified and characterized a region in the NiV-G stalk C-terminal domain that links receptor binding to fusion triggering via several important glycoprotein functions. These findings advance our understanding of the membrane fusion-triggering mechanism(s) of the henipaviruses and the paramyxoviruses.
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Bradel-Tretheway
authors.affiliation: Department of Chemistry, Washington State University, Pullman, Washington, USA.
authors.forename: Abrrey I
authors.initials: AI
authors.lastname: Monreal
authors.affiliation: Department of Chemistry, Washington State University, Pullman, Washington, USA.
authors.forename: Jonel P
authors.initials: JP
authors.lastname: Saludes
authors.affiliation: Food, Nutrition and Health Program, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USA.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Nicola
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USA haguilar@vetmed.wsu.edu.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Aguilar
mesh_terms: D000818:Animals; D002460:Cell Line; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D045405:Nipah Virus / Q000502:physiology*; D011487:Protein Conformation; D015678:Viral Structural Proteins / Q000737:chemistry / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D006023:Glycoproteins; D015678:Viral Structural Proteins