Individual N-Glycans Added at Intervals along the Stalk of the Nipah Virus G Protein Prevent Fusion but Do Not Block the Interaction with the Homologous F Protein

Zhu, Qing; Biering, Scott B.; Mirza, Anne M.; Grasseschi, Brittany A.; Mahon, Paul J.; Lee, Benhur; Aguilar, Hector C.; Iorio, Ronald M.

doi:10.1128/jvi.03084-12

Cited by 18 publications

(17 citation statements)

References 50 publications

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“…3A), indicating that these mutations had no significant effect on the first conformational change at the membranedistal portion of the NiV-G head. EphrinB2 binding to NiV-G also induces a roughly 2-fold increase in Mab45 binding to NiV-G (step 2), a step important for F triggering (28,30,31,34). We previously mapped the Mab45 epitope to region ␤6S4/␤1H1 (aa 177 to 194) at the base of the NiV-G head (28).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, it has been recently shown for several paramyxoviruses, including our report for NiV, that headless HN-H-G mutant proteins that carry an intact 4HB tetramerization domain are still able to trigger cell-cell fusion with their cognate F, suggesting that the stalk domain of the attachment protein has F-triggering features in common within the paramyxovirus family (25)(26)(27)(28). Although the crystal structures of the NiV-and HeV-G stalk domains are unsolved, several studies including site-directed mutagenesis, construction of NDV/NiV chimeras, and removal or addition of N-glycan moieties have suggested that NiV-and HeV-G stalk domains are important in modulating fusion and G oligomerization (18,(28)(29)(30)(31). We recently reported a three-step spatiotemporal mechanism of receptor-induced NiV membrane fusion.…”

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confidence: 99%

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Nipah Virus Attachment Glycoprotein Stalk C-Terminal Region Links Receptor Binding to Fusion Triggering

Liu

Bradel-Tretheway

Monreal

et al. 2015

J Virol

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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. IMPORTANCEThe 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. N ipah virus (NiV) and Hendra virus (HeV) are two important emergent viruses in the genus Henipavirus (HNV) within the Paramyxoviridae family, which includes other important pathogens such as measles virus (MeV), mumps virus, Newcastle disease virus (NDV), human parainfluenza virus (PIV), and respiratory syncytial virus. NiV is an emergent zoonotic pathogen present at high frequencies in its natural reservoir, fruit bats, and can be transmitted from animal to animal, animal to human, and human to human (1). NiV...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Nipah Virus Attachment Glycoprotein Stalk C-Terminal Region Links Receptor Binding to Fusion Triggering

Liu

Bradel-Tretheway

Monreal

et al. 2015

J Virol

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“…Although individual residues critical for F interaction and F activation have been determined for HN, H, or G stalk domains, it is becoming increasingly clear that F interaction with HN, H, or G stalk domain alone does not lead to F activation. Although these two aspects of the F triggering process are functionally linked, they can be separated by targeted mutagenesis (62,70,71; reviewed in reference 72).…”

Section: Discussionmentioning

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

116

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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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“…All chimeric proteins contained a carboxy-terminal FLAG epitope (M74-G-FLAG ED, NiV-G-FLAG ED): M74-G ED consists of the amino acid (aa) residues 1 to 70 of NiV-G and aa 88 to 632 of M74-G, whereas NiV-G ED consists of aa 1 to 87 of M74-G and aa 71 to 602 of NiV-G. While the sequence of the NiV-G ED was derived from published data (25,26), the definitions of the NiV-G TD and CT as well as those of the M74-G ED, TD, and CT were based on the prediction of transmembrane regions by the online tool HMMTOP (www.enzim.hu/hmmtop/).…”

Section: Methodsmentioning

confidence: 99%

Attachment Protein G of an African Bat Henipavirus Is Differentially Restricted in Chiropteran and Nonchiropteran Cells

Krüger

Hoffmann

Drexler

et al. 2014

J Virol

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Individual N-Glycans Added at Intervals along the Stalk of the Nipah Virus G Protein Prevent Fusion but Do Not Block the Interaction with the Homologous F Protein

Cited by 18 publications

References 50 publications

Nipah Virus Attachment Glycoprotein Stalk C-Terminal Region Links Receptor Binding to Fusion Triggering

Nipah Virus Attachment Glycoprotein Stalk C-Terminal Region Links Receptor Binding to Fusion Triggering

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

Attachment Protein G of an African Bat Henipavirus Is Differentially Restricted in Chiropteran and Nonchiropteran Cells

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