Parainfluenza virus type 3 hemagglutinin-neuraminidase

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=== Carbohydrate ligands ===
=== Carbohydrate ligands ===
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Parainfluenza virus type 3 hemagglutinin-neuraminidase binds sialylated glycans. The sialic acid is linked &alpha;2-3 to galactose. The minimal binding motif is a pentasaccharide if there are no modifdications, but smaller units bind if there is sulfation or fucosylation, as shown in the figure below <ref>Amonsen, M., Smith, D.F., Cummings, R.D., and Air, G.M. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with {alpha}2-3 linked sialic acid that are distinct from those bound by H5 avian influenza hemagglutinin. J Virol 81:8341-8345.</ref>
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Parainfluenza virus type 3 hemagglutinin-neuraminidase binds sialylated glycans. The sialic acid is linked &alpha;2-3 to galactose. The minimal binding motif is a pentasaccharide if there are no modifications, but smaller units bind if there is sulfation or fucosylation, as shown in the figure below <ref>Amonsen, M., Smith, D.F., Cummings, R.D., and Air, G.M. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with {alpha}2-3 linked sialic acid that are distinct from those bound by H5 avian influenza hemagglutinin. J Virol 81:8341-8345.</ref>
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[[File: PIV3glycans.png]]
[[File: PIV3glycans.png]]

Revision as of 21:14, 8 July 2010

Like influenza, the paramyxoviruses show hemagglutinin and neuraminidase (HN) activities, but in this case, the two activities reside on the same glycoprotein. Structures of three paramyxovirus HNs have been determined; they are Newcastle Disease virus, human parainfluenza type 3, and human parainfluenza type 5 (formerly called SV5). The structures show an identical fold to influenza neuraminidase, with an NA active site that is almost identical to that of influenza. Thus HN is a sialidase that also binds sialylated glycans as receptors for cell entry. Whether there is a separate binding site has been a subject of great controversy that is still not solved. NDV shows sialic acid bound at a second site but the second molecule has not been seen in hPIV3 or hPIV5 HN structures. Mutagenesis and antibody studies suggest one site in some strains and two sites in others, while a second site appeared to be created in hPIV3 by mutagenesis. This lack of understanding of how paramyxoviruses enter cells and how new viruses are released has severely hampered development to antivirals targeted to these activities. CFG PIs are investigating the binding and cleavage specificities of HNs and mutants.

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) contributing to the understanding of parainfluenza virus type 3 HN include: Gillian Air, Theodore Jardetsky, Matteo Porotto, Charles Russell

Progress toward understanding this GBP paradigm

Carbohydrate ligands

Parainfluenza virus type 3 hemagglutinin-neuraminidase binds sialylated glycans. The sialic acid is linked α2-3 to galactose. The minimal binding motif is a pentasaccharide if there are no modifications, but smaller units bind if there is sulfation or fucosylation, as shown in the figure below [1]
File: PIV3glycans.png Media:Example.ogg

Cellular expression of GBP and ligands

Parainfluenza virus type 3 hemagglutinin-neuraminidase is expressed by paramyxoviruses.

Biosynthesis of ligands


Structure

The crystal structure of a hPIV3 HN has been determined in dimer form [2] and serves as the model for glycan binding and neuraminidase studies.
The subunits are colored green and blue. A molecule of inhibitor 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid is bound to the active site of each subunit (stick model: C, O and N atoms are gray, red and blue respectively). The figure was made using PyMol (Delano Scientific) from PDB file 1V3D.
file: 1V3D.png

Biological roles of GBP-ligand interaction


CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "parainfluenza".

Glycan profiling


Glycogene microarray


Knockout mouse lines


Glycan array

There have been many resource requests for glycan array screening of paramyxovirus hemagglutinin-neuraminidase (for example, click here). To see all glycan array results for parainfluenza hemagglutinin-neuraminidase, click here. For glycan array results of other paramyxovirus HNs, click here.

Related GBPs

  • Other paramyxovirus HNs: some appear to have one site that carries out both activities; others appear to have separate sites.
  • Human parainfluenza types 1, 2, 4 and 5
  • Newcastle Disease virus
  • Mumps virus

References

  1. Amonsen, M., Smith, D.F., Cummings, R.D., and Air, G.M. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with {alpha}2-3 linked sialic acid that are distinct from those bound by H5 avian influenza hemagglutinin. J Virol 81:8341-8345.
  2. Lawrence MC, Borg NA, Streltsov VA, Pilling PA, Epa VC, Varghese JN, McKimm-Breschkin JL, Colman PM. (2004) Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. J Mol Biol 335(5): 1343-57.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Gillian Air, James Paulson, Matteo Porotto

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