Ionic dependence of the sialidase activity of hemagglutinin-neuraminidase glycoprotein in Newcastle Disease Virus membrane

Barroso, Isabel Muñoz; Moralejo, Francisco J.; Villar, Enrique

doi:10.1042/bst022366s

Cited by 4 publications

(3 citation statements)

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“…Indeed, while the glycoprotein presents some features that are conserved with paramyxoviral RBPs with known HN functionality, including a conserved cation binding site ( SI Appendix , Fig. S2) (36, 63, 64, 68) and residues that would contribute to recognition of the glycerol moeity of sialic acid (Fig. 4 A and B ), the overall configuration of the putative active site is incompatible with known modes of sialic acid recognition.…”

Section: Resultsmentioning

confidence: 99%

A structure-based rationale for sialic acid independent host-cell entry of Sosuga virus

Stelfox

Bowden

2019

Proc. Natl. Acad. Sci. U.S.A.

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The bat-borne paramyxovirus, Sosuga virus (SosV), is one of many paramyxoviruses recently identified and classified within the newly established genus Pararubulavirus, family Paramyxoviridae. The envelope surface of SosV presents a receptor-binding protein (RBP), SosV-RBP, which facilitates host-cell attachment and entry. Unlike closely related hemagglutinin neuraminidase RBPs from other genera of the Paramyxoviridae, SosV-RBP and other pararubulavirus RBPs lack many of the stringently conserved residues required for sialic acid recognition and hydrolysis. We determined the crystal structure of the globular head region of SosV-RBP, revealing that while the glycoprotein presents a classical paramyxoviral six-bladed β-propeller fold and structurally classifies in close proximity to paramyxoviral RBPs with hemagglutininneuraminidase (HN) functionality, it presents a receptor-binding face incongruent with sialic acid recognition. Hemadsorption and neuraminidase activity analysis confirms the limited capacity of SosV-RBP to interact with sialic acid in vitro and indicates that SosV-RBP undergoes a nonclassical route of host-cell entry. The close overall structural conservation of SosV-RBP with other classical HN RBPs supports a model by which pararubulaviruses only recently diverged from sialic acid binding functionality.virus-host interaction | viral attachment | paramyxovirus | structure | glycoprotein

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Section: Resultsmentioning

confidence: 99%

A structure-based rationale for sialic acid independent host-cell entry of Sosuga virus

Stelfox

Bowden

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Interactions with all three hydroxyl groups of the glycerol chain have never been observed in other viral or bacterial NAs so far studied 17 , which suggests that in HN such interactions are a key determinant of substrate recognition. Glu 258 and Tyr 262 lie on a helix (α1) that is stabilized by the calcium ion, and it is interesting to note that removal of Ca 2+ completely abolishes enzyme activity 24 .…”

Section: Identifying the Catalytic Sitementioning

confidence: 99%

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et al. 2000

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Paramyxoviruses are the main cause of respiratory disease in children. One of two viral surface glycoproteins, the hemagglutinin-neuraminidase (HN), has several functions in addition to being the major surface antigen that induces neutralizing antibodies. Here we present the crystal structures of Newcastle disease virus HN alone and in complex with either an inhibitor or with the beta-anomer of sialic acid. The inhibitor complex reveals a typical neuraminidase active site within a beta-propeller fold. Comparison of the structures of the two complexes reveal differences in the active site, suggesting that the catalytic site is activated by a conformational switch. This site may provide both sialic acid binding and hydrolysis functions since there is no evidence for a second sialic acid binding site in HN. Evidence for a single site with dual functions is examined and supported by mutagenesis studies. The structure provides the basis for the structure-based design of inhibitors for a range of paramyxovirus-induced diseases.

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“…A divalent anion at the dimer-dimer interface is observed only in the MuV-HN head domain tetramer but not in the HN tetramers of hPIV3, PIV5, and NDV (3,7,8). Interestingly, a Ca 2ϩ ion is found at the common site within each HN monomer of hPIV3, PIV5, and NDV but not MuV, and it is reported that Ca 2ϩ is required for neuraminidase activity in NDV (26). An SO 4…”

Section: Discussionmentioning

confidence: 94%

Disruption of the Dimer-Dimer Interaction of the Mumps Virus Attachment Protein Head Domain, Aided by an Anion Located at the Interface, Compromises Membrane Fusion Triggering

Kubota

Okabe

Nakakita

et al. 2020

J Virol

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Mumps virus (MuV), an enveloped negative-strand RNA virus belonging to the family Paramyxoviridae, enters the host cell through membrane fusion mediated by two viral envelope proteins, an attachment protein hemagglutinin-neuraminidase (MuV-HN) and a fusion (F) protein. However, how the binding of MuV-HN to glycan receptors triggers membrane fusion is not well understood. The crystal structure of the MuV-HN head domain forms a tetramer (dimer of dimers) like other paramyxovirus attachment proteins. In the structure, a sulfate ion (SO42−) was found at the interface between two dimers, which may be replaced by a hydrogen phosphate ion (HPO42−) under physiological conditions. The anion is captured by the side chain of a positively charged arginine residue at position 139 of one monomer each from both dimers. Substitution of alanine or lysine for arginine at this position compromised the fusion support activity of MuV-HN without affecting its cell surface expression, glycan-receptor binding, and interaction with the F protein. Furthermore, the substitution appeared to affect the tetramer formation of the head domain as revealed by blue native-PAGE analysis. These results, together with our previous similar findings with the measles virus attachment protein head domain, suggest that the dimer-dimer interaction within the tetramer may play an important role in triggering membrane fusion during paramyxovirus entry. IMPORTANCE Despite the use of effective live vaccines, mumps outbreaks still occur worldwide. Mumps virus (MuV) infection typically causes flu-like symptoms and parotid gland swelling but sometimes leads to orchitis, oophoritis, and neurological complications, such as meningitis, encephalitis, and deafness. MuV enters the host cell through membrane fusion mediated by two viral proteins, a receptor-binding attachment protein, and a fusion protein, but its detailed mechanism is not fully understood. In this study, we show that the tetramer (dimer of dimers) formation of the MuV attachment protein head domain is supported by an anion located at the interface between two dimers and that the dimer-dimer interaction plays an important role in triggering the activation of the fusion protein and causing membrane fusion. These results not only further our understanding of MuV entry but provide useful information about a possible target for antiviral drugs.

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Ionic dependence of the sialidase activity of hemagglutinin-neuraminidase glycoprotein in Newcastle Disease Virus membrane

Cited by 4 publications

References 0 publications

A structure-based rationale for sialic acid independent host-cell entry of Sosuga virus

A structure-based rationale for sialic acid independent host-cell entry of Sosuga virus

Untitled

Disruption of the Dimer-Dimer Interaction of the Mumps Virus Attachment Protein Head Domain, Aided by an Anion Located at the Interface, Compromises Membrane Fusion Triggering

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