A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F)

Aguilar, Hector C.; Ataman, Zeynep Akyol; Aspericueta, Vanessa; Fang, Angela Q.; Stroud, Matthew J.; Negrete, Oscar; Kammerer, Richard A.; Lee, Benhur

doi:10.1074/jbc.m807469200

Cited by 86 publications

(179 citation statements)

References 44 publications

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“…Recently obtained atomic structures of HN stalk domains from NDV HN (23) and PIV5 HN (29) showed the stalks to be four-helix bundles (4HB), possessing a C-terminal linear coiled-coil region with an 11-mer hydrophobic central core repeat, adjacent to an N-terminal left-handed supercoiled region with 7-mer repeats. A large body of data suggests that F interacts with the attachment protein through the HN, H, or G stalk domains (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41); however, the exact nature of the interaction and nature of the F activation process are not clear.…”

Section: Paramyxoviruses Are a Large Family Of Membrane-enveloped Negmentioning

confidence: 99%

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

Bose

Song

Jardetzky

et al. 2014

J Virol

113

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Paramyxoviruses are a large family of membrane-enveloped negative-stranded RNA viruses causing important diseases in humans and animals. Two viral integral membrane glycoproteins (fusion [F] and attachment [HN, H, or G]) mediate a concerted process of host receptor recognition, followed by the fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. However, the sequence of events that closely links the timing of receptor recognition by HN, H, or G and the "triggering" interaction of the attachment protein with F is unclear. F activation results in F undergoing a series of irreversible conformational rearrangements to bring about membrane merger and virus entry. By extensive study of properties of multiple paramyxovirus HN proteins, we show that key features of F activation, including the F-activating regions of HN proteins, flexibility within this F-activating region, and changes in globular head-stalk interactions are highly conserved. These results, together with functionally active "headless" mumps and Newcastle disease virus HN proteins, provide insights into the F-triggering process. Based on these data and very recently published data for morbillivirus H and henipavirus G proteins, we extend our recently proposed "stalk exposure model" to other paramyxoviruses and propose an "induced fit" hypothesis for F-HN/H/G interactions as conserved core mechanisms of paramyxovirus-mediated membrane fusion. HN, H, or G]) mediate a concerted process of host receptor recognition, followed by the fusion of viral and cellular membranes. We describe here the molecular mechanism by which HN activates the F protein such that virus-cell fusion is controlled and occurs at the right time and the right place. We extend our recently proposed "stalk exposure model" first proposed for parainfluenza virus 5 to other paramyxoviruses and propose an "induced fit" hypothesis for F-HN/H/G interactions as conserved core mechanisms of paramyxovirusmediated membrane fusion. IMPORTANCE Paramyxoviruses are a large family of membrane-enveloped negative-stranded RNA viruses causing important diseases in humans and animals. Two viral integral membrane glycoproteins (fusion [F] and attachment [

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Section: Paramyxoviruses Are a Large Family Of Membrane-enveloped Negmentioning

confidence: 99%

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

Bose

Song

Jardetzky

et al. 2014

J Virol

113

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“…Five of the residues that constitute the RBD-RBD interface in the ephrin-bound state, L 202 , S 204 , T 206 , V 210 , and G 211 , have been mutated to alanines in experiments, and all of these mutations impact G-stimulation negatively (36). In particular, the triple mutation, V 209 V 210 G 211 / AAA, leads to complete loss in NiV fusion, but without affecting ephrin binding.…”

Section: Stimulation-deficient Mutant Dimermentioning

confidence: 99%

“…The residues VVG are part of the RBD, and distant from both the ephrin-RDB and RBD-FAD interfaces. Their mutation to alanines affects neither the expression of G nor its binding to ephrin (36). Yet, the triple mutation abolishes the ability of G to activate F. Consequently, this triple mutation makes Nipah nonfusogenic by hindering G stimulation.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Dutta¹,

Siddiqui²,

Botlani³

et al. 2016

Biophysical Journal

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Nipah is an emerging paramyxovirus that is of serious concern to human health. It invades host cells using two of its membrane proteins-G and F. G binds to host ephrins and this stimulates G to activate F. Upon activation, F mediates virus-host membrane fusion. Here we focus on mechanisms that underlie the stimulation of G by ephrins. Experiments show that G interacts with ephrin and F through separate sites located on two different domains, the receptor binding domain (RBD) and the F activation domain (FAD). No models explain this allosteric coupling. In fact, the analogous mechanisms in other paramyxoviruses also remain undetermined. The structural organization of G is such that allosteric coupling must involve at least one of the two interfaces-the RBD-FAD interface and/or the RBD-RBD interface. Here we examine using molecular dynamics the effect of ephrin binding on the RBD-RBD interface. We find that despite inducing small changes in individual RBDs, ephrin reorients the RBD-RBD interface extensively, and in a manner that will enhance solvent exposure of the FAD. While this finding supports a proposed model of G stimulation, we also find from additional simulations that ephrin induces a similar RBD-RBD reorientation in a stimulation-deficient G mutant, V 209 VG / AAA. Together, our simulations suggest that while inter-RBD reorientation may be important, it is not, by itself, a sufficient condition for G stimulation. Additionally, we find that the mutation affects the conformational ensemble of RBD globally, including the RBD-FAD interface, suggesting the latter's role in G stimulation. Because ephrin induces small changes in individual RBDs, a proper analysis of conformational ensembles required that they are compared directly-we employ a method we developed recently, which we now release at SimTK, and show that it also performs excellently for non-Gaussian distributions.

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“…Henipavirus, like many paramyxoviruses, requires the presence of two surface glycoproteins for virus-cell and cell-cell fusion (8,9,36): the fusion protein, F, which mediates the membrane fusion event, and the attachment protein, G, which binds cellular receptors ephrin B2 (6,22) and ephrin B3 (23) and which is required for F-mediated membrane fusion. Interactions between the fusion and attachment proteins of a number of paramyxoviruses have been observed previously (30,33,35), and interactions between the henipavirus F and G proteins have been demonstrated by coimmunoprecipitation (1)(2)(3)(4)(5)18). However, important questions remain concerning the timing of these interactions and the mechanism by which the attachment protein regulates F-mediated fusion.…”

mentioning

confidence: 99%

Differential Rates of Protein Folding and Cellular Trafficking for the Hendra Virus F and G Proteins: Implications for F-G Complex Formation

Whitman

Smith

Dutch

2009

J Virol

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Hendra virus F protein-promoted membrane fusion requires the presence of the viral attachment protein, G. However, events leading to the association of these glycoproteins remain unclear. Results presented here demonstrate that Hendra virus G undergoes slower secretory pathway trafficking than is observed for Hendra virus F. This slowed trafficking is not dependent on the G protein cytoplasmic tail, the presence of the G receptor ephrin B2, or interaction with other viral proteins. Instead, Hendra virus G was found to undergo intrinsically slow oligomerization within the endoplasmic reticulum. These results suggest that the critical F-G interactions occur only after the initial steps of synthesis and cellular transport.

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A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F)

Cited by 86 publications

References 44 publications

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Differential Rates of Protein Folding and Cellular Trafficking for the Hendra Virus F and G Proteins: Implications for F-G Complex Formation

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