Viruses From Structure to Biology


But the hemagglutinin is not the only protein on the surface of the influenza virus particle. The other protein, neuraminidase, plays an essential role in the life cycle of the virus and has its own interesting history. According to Graeme Laver:

"The neuraminidase story started in the 1940s when George Hirst, working in the Rockefeller Institute in New York, reported that when allantoic fluid from flu virus infected eggs was mixed with red blood cells in ice the cells were very heavily agglutinated. If these agglutinated cells were warmed to 37 degrees they dispersed and could not be re-agglutinated in the cold by fresh virus. Hirst took this to mean that the virus had an enzyme which destroyed receptors for the virus on the red cell. Shortly after, MacFarlane Burnet (the same MacFarlane Burnet who demonstrated that there were several strains of poliovirus), in the Walter and Eliza Hall Institute in Melbourne, found that Vibrio cholerae secreted an enzyme which did the same thing and this enzyme became known as receptor destroying enzyme or RDE. Burnet was immensely curious about the nature of the substrate for RDE and persuaded (ordered, more likely !) a biochemist, Alfred Gottschalk who was working on yeast fermentation in the Institute, to stop working on yeast and find out what reaction RDE catalyzed."

Gottschalk discovered that the reaction product produced by the RDE was sialic acid (N-acetyl neuraminic acid) and that RDE
is a sialidase or neuraminidase. Then Graeme explained how the activities of neuraminidase and hemagglutinin were distinguished:

"It had been generally accepted that the agglutination of red cells by flu virus was due to the sialidase (neuraminidase) on the virus binding to its substrate, sialic acid, on the surface of the cell. This idea persisted for some time until, in 1961, the first doubts started to appear. Mayron and his colleagues showed that a soluble sialidase could be separated from the PR8 influenza virus and it did not adsorb to red cells (Mayron, L. W., Robert, B., Winzler, R. J. and Rafelson, M. E. Arch. Biochem. Biophys. 92: 475- 483, 1961). In 1962 in a more elegant experiment, Hans Noll found that treating flu B virus with trypsin liberated almost 100% of the neuraminidase as a soluble molecule with sedimentation coefficient of 9S (about 200,000 Mol Wt) leaving all of the haemagglutinin activity still associated with the virus particle (Noll, H., Aoyagi, T. and Orlando, J. Virology 18: 154-157, 1962)."

The structure of neuraminidase was solved in 1983 by J. N. Varghese, W. G. Laver and P. M. Colman (Nature 303:35-40). In the same issue of Nature Don Wiley commented on the structure writing that: "Viewed from above the head, each monomer consists of six of the four-stranded sheets arrayed like the petals of a flower but twisted like the blades of a pinwheel. A new category of tertiary structure is born".

Neuraminidase belongs to the class of proteins embedded in the membrane at the amino terminus. The box-like head of the neuraminidase is connected to a stalk that comprises the amino terminal part of the protein and includes the membrane-spanning domain. The stalk had been removed by protease treatment for crystallization and its structure remains unknown.

The structures of the plant RNA viruses and the picornaviruses had been remarkable in their similarity, not so the hemagglutinin and neuraminidase. Don Wiley wrote: "The topology of folding in the NA is quite unrelated to that in the HA, however, so suggestions that the two sialic acid-binding proteins of the virus may have evolved from a common ancestor can safely be dismissed".

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| Introduction | Some historical highlights: structural virology and virology |
| Solving the Structure of Icosahedral Plant Viruses | Picornavirus Structure | Poliovirus | Polio
The Influenza Virus Hemagglutinin
| The Influenza Virus Neuraminidase |
Issues of Science and Society |contributors|
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