title: Unraveling a three-step spatiotemporal mechanism of triggering of receptor-induced Nipah virus fusion and cell entry.
abstract: Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, United States of America.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Stone
authors.forename: Birgit
authors.initials: B
authors.lastname: Bradel-Tretheway
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dabundo
authors.forename: Javier A
authors.initials: JA
authors.lastname: Benavides Montano
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santos-Montanez
authors.forename: Scott B
authors.initials: SB
authors.lastname: Biering
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Nicola
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Iorio
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Lu
authors.forename: Hector C
authors.initials: HC
authors.lastname: Aguilar
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D045464:Henipavirus Infections / Q000235:genetics / Q000378:metabolism; D050576:Membrane Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D045405:Nipah Virus / Q000502:physiology*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D006023:Glycoproteins; D050576:Membrane Fusion Proteins; D011991:Receptors, Virus; D014764:Viral Proteins