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PubMed2001

Response of domestic geese to lentogenic and velogenic strains of Newcastle disease virus.

A total of 54 domestic white meat-type geese were included in vaccination/challenge trials to evaluate susceptibility to disease and humoral immune responses using the haemagglutination inhibition (HI) and virus neutralization (VN) tests against Newcastle disease (ND). Two groups of twenty geese, five weeks of age, were conjunctivally vaccinated with either 100 x 10(6) or 2.5 x 10(6) EID50 (egg infectious dose 50 per cent) per bird of live La Sota virus, respectively, and 14 geese remained unvaccinated. At 15 weeks of age all vaccinated geese and seven unvaccinated geese were subcutaneously injected with 0.5 ml of inactivated oil emulsion ND vaccine, whereas seven geese remained as negative controls. At an age of 20 weeks, all 54 geese were challenged with 10(8.0) EID50 per bird of the viscerotropic velogenic NDV strain Herts 33/56. Live virus application as well as the oil emulsion vaccine did not induce discernible clinical signs and have no detrimental effect on body weight gains. At days 1, 3, 5, 8, 13, 16, 20, 23 and 27 after the application of lentogenic vaccine pharyngeal and cloacal swabs were taken, after challenge samples were taken at days 2, 5 and 8. Lentogenic as well as velogenic virus were never reisolated. Low and shortlived antibody responses post vaccination were equally well measured in HI and VN tests. Only two out of seven unvaccinated but challenged geese developed signs of ND whereas all vaccinated/challenged geese remained normal but developed high to moderate levels of HI and VN antibodies. Since domestic geese do not readily excrete NDV's in detectable amounts and since they do not contain detectable amounts of the challenge virus fourteen days post challenge in their tissues the assumption is promoted that geese do not play a major role in the epidemiology of Newcastle disease.

Animals↗
PubMed2003

Crystallization and preliminary X-ray diffraction analysis of post-fusion six-helix bundle core structure from Newcastle disease virus F protein.

Fusion of virus members from the Paramyxoviridae family involves two glycoproteins. They are termed attachment glycoprotein (HN, H or G) and fusion protein (F). The F protein contains two highly conserved heptad-repeat (HR) regions, HR1 and HR2. Through conformational changes in the F protein, HR1 and HR2 are believed to form a stable six-helix coiled-coil bundle during the membrane-fusion process. However, no crystal structure has yet been documented for this state in the Newcastle disease virus (NDV, a member of the Paramyxoviridae family) F protein, despite the recent success on its F(0) crystal structure (Chen et al., 2001), which was thought to represent the pre-fusion conformation of F glycoprotein. In this study, a single-chain polypeptide constructed by linking two truncated HR regions of the NDV F protein has been expressed, purified and crystallized by means of the hanging- or sitting-drop vapour-diffusion method. Crystals in hexagonal and trapezoid forms with a resolution limit of 2.6 A were obtained. These crystals belonged to space group C2, with unit-cell parameters a = 66.4, b = 38.2, c = 102.0 A, beta = 100.2 degrees. Crystals in the rhombic form with a resolution limit of 2.5 A were also obtained. These crystals belonged to space group P2(1), with unit-cell parameters a = 59.0, b = 31.9, c = 62.3 A, beta = 117.0 degrees. This will add to the repertoire of viral fusion protein post-fusion state structures and help further the understanding of the molecular mechanism of enveloped virus fusion.

Crystallization↗
PubMed2004

Second sialic acid binding site in Newcastle disease virus hemagglutinin-neuraminidase: implications for fusion.

Paramyxoviruses are the leading cause of respiratory disease in children. Several paramyxoviruses possess a surface glycoprotein, the hemagglutinin-neuraminidase (HN), that is involved in attachment to sialic acid receptors, promotion of fusion, and removal of sialic acid from infected cells and progeny virions. Previously we showed that Newcastle disease virus (NDV) HN contained a pliable sialic acid recognition site that could take two states, a binding state and a catalytic state. Here we present evidence for a second sialic acid binding site at the dimer interface of HN and present a model for its involvement in cell fusion. Three different crystal forms of NDV HN now reveal identical tetrameric arrangements of HN monomers, perhaps indicative of the tetramer association found on the viral surface.

Binding Sites↗
PubMed2003

Design and analysis of post-fusion 6-helix bundle of heptad repeat regions from Newcastle disease virus F protein.

Fusion of paramyxovirus to the cell involves receptor binding of the HN glycoprotein and a number of conformational changes of F glycoprotein. The F protein is expressed as a homotrimer on the virus surface. In the present model, there are at least three conformations of F protein, i.e. native form, pre-hairpin intermediate and the post-fusion state. In the post-fusion state, the two highly conserved heptad repeat (HR) regions of F protein form a stable 6-helix coiled-coil bundle. However, no crystal structure is known for this state for the Newcastle disease virus, although the crystal structure of the F protein native form has been solved recently. Here we deployed an Escherichia coli in vitro expression system to engineer this 6-helix bundle by fusion of either the two HR regions (HR1, linker and HR2) or linking the 6-helix [3 x (HR1, linker and HR2)] together as a single chain. Subsequently, both of them form a stable 6-helix bundle in vitro judging by gel filtration and chemical cross-linking and the proteins show salient features of an alpha-helix structure. Crystals diffracting X-rays have been obtained from both protein preparations and the structure determination is under way. This method could be used for crystallization of the post-fusion state HR structures of other viruses.

Amino Acid Sequence↗
PubMed2003

Interacting domains of the HN and F proteins of newcastle disease virus.

The activation of most paramyxovirus fusion proteins (F proteins) requires not only cleavage of F(0) to F(1) and F(2) but also coexpression of the homologous attachment protein, hemagglutinin-neuraminidase (HN) or hemagglutinin (H). The type specificity requirement for HN or H protein coexpression strongly suggests that an interaction between HN and F proteins is required for fusion, and studies of chimeric HN proteins have implicated the membrane-proximal ectodomain in this interaction. Using biotin-labeled peptides with sequences of the Newcastle disease virus (NDV) F protein heptad repeat 2 (HR2) domain, we detected a specific interaction with amino acids 124 to 152 from the NDV HN protein. Biotin-labeled HR2 peptides bound to glutathione S-transferase (GST) fusion proteins containing these HN protein sequences but not to GST or to GST containing HN protein sequences corresponding to amino acids 49 to 118. To verify the functional significance of the interaction, two point mutations in the HN protein gene, I133L and L140A, were made individually by site-specific mutagenesis to produce two mutant proteins. These mutations inhibited the fusion promotion activities of the proteins without significantly affecting their surface expression, attachment activities, or neuraminidase activities. Furthermore, these changes in the sequence of amino acids 124 to 152 in the GST-HN fusion protein that bound HR2 peptides affected the binding of the peptides. These results are consistent with the hypothesis that HN protein binds to the F protein HR2 domain, an interaction important for the fusion promotion activity of the HN protein.

Animals↗
PubMed2001

The structure of the fusion glycoprotein of Newcastle disease virus suggests a novel paradigm for the molecular mechanism of membrane fusion.

BACKGROUND: Membrane fusion within the Paramyxoviridae family of viruses is mediated by a surface glycoprotein termed the "F", or fusion, protein. Membrane fusion is assumed to involve a series of structural transitions of F from a metastable (prefusion) state to a highly stable (postfusion) state. No detail is available at the atomic level regarding the metastable form of these proteins or regarding the transitions accompanying fusion. RESULTS: The three-dimensional structure of the fusion protein of Newcastle disease virus (NDV-F) has been determined. The trimeric NDV-F molecule is organized into head, neck, and stalk regions. The head is comprised of a highly twisted beta domain and an additional immunoglobulin-like beta domain. The neck is formed by the C-terminal extension of the heptad repeat region HR-A, capped by a four-helical bundle. The C terminus of HR-A is encased by a further helix HR-C and a 4-stranded beta sheet. The stalk is formed by the remaining visible portion of HR-A and by polypeptide immediately N-terminal to the C-terminal heptad repeat region HR-B. An axial channel extends through the head and neck and is fenestrated by three large radial channels located approximately at the head-neck interface. CONCLUSION: We propose that prior to fusion activation, the hydrophobic fusion peptides in NDV-F are sequestered within the radial channels within the head, with the central HR-A coiled coil being only partly formed. Fusion activation then involves, inter alia, the assembly of a complete HR-A coiled coil, with the fusion peptides and transmembrane anchors being brought into close proximity. The structure of NDV-F is fundamentally different than that of influenza virus hemagglutinin, in that the central coiled coil is in the opposite orientation with respect to the viral membrane.

Amino Acid Sequence↗
PubMed2001

Mutational analysis of the membrane proximal heptad repeat of the newcastle disease virus fusion protein.

Paramyxovirus fusion proteins have two heptad repeat domains, HR1 and HR2, that have been implicated in the fusion activity of the protein. Peptides from these two domains form a six-stranded, coiled-coil with the HR1 sequences forming a central trimer and three molecules of the HR2 helix located within the grooves in the central trimer (Baker et al., 1999, Mol. Cell 3, 309; Zhao et al. 2000, Proc. Natl. Acad. Sci. USA 97, 14172). Nonconservative mutations were made in the HR2 domain of the Newcastle disease virus fusion protein in residues that are likely to form contacts with the HR1 core trimer. These residues form the hydrophobic face of the helix and adjacent residues ("a" and "g" positions in the HR2 helical wheel structure). Mutant proteins were characterized for effects on synthesis, steady-state levels, proteolytic cleavage, and surface expression as well as fusion activity as measured by syncytia formation, content mixing, and lipid mixing. While all mutant proteins were transport competent and proteolytically cleaved, these mutations did variously affect fusion activity of the protein. Nonconservative mutations in the "g" position had no effect on fusion. In contrast, single changes in the middle "a" position of HR2 inhibited lipid mixing, content mixing, and syncytia formation. A single mutation in the more carboxyl-terminal "a" position had minimal effects on lipid mixing but did inhibit content mixing and syncytia formation. These results are consistent with the idea that the HR2 domain is involved in posttranslational interactions with HR1 that mediate the close approach of membranes. These results also suggest that the HR2 domain, particularly the carboxyl-terminal region, plays an additional role in fusion, a role related to content mixing and syncytia formation.

Amino Acid Sequence↗
PubMed1999

Amino acid substitutions in a conserved region in the stalk of the Newcastle disease virus HN glycoprotein spike impair its neuraminidase activity in the globular domain.

The ectodomain of the paramyxovirus haemagglutinin-neuraminidase (HN) glycoprotein spike can be divided into two regions: a membrane-proximal, stalk-like structure and a terminal globular domain. The latter contains all the antibody recognition sites of the protein, as well as its receptor recognition and neuraminidase (NA) active sites. These two activities of the protein can be separated by monoclonal antibody functional inhibition studies and mutations in the globular domain. Herein, we show that mutation of several conserved residues in the stalk of the Newcastle disease virus HN protein markedly decrease its NA activity without a significant effect on receptor recognition. Thus, mutations in the stalk, distant from the NA active site in the globular domain, can also separate attachment and NA. These results add to an increasing body of evidence that the NA activity of this protein is dependent on an intact stalk structure.

Adsorption↗