Research

Protein intrinsic disorder and influenza virulence: the 1918 H1N1 and H5N1 viruses

Gerard Kian-Meng Goh^1,4 , A Keith Dunker¹ and Vladimir N Uversky^1,2,3

¹  Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

²  Institute for Intrinsically Disordered Protein Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

³  Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

⁴  Institute of Molecular and Cell Biology, Singapore 138673, Republic of Singapore

author email corresponding author email

Virology Journal 2009, 6:69doi:10.1186/1743-422X-6-69

Published:	3 June 2009

Abstract

Background

The 1918 H1N1 virus was a highly virulent strain that killed 20–50 million people. The cause of its virulence remains poorly understood.

Methods

Intrinsic disorder predictor PONDR^® VLXT was used to compare various influenza subtypes and strains. Three-dimensional models using data from X-ray crystallographic studies annotated with disorder prediction were used to characterize the proteins.

Results

The protein of interest is hemagglutin (HA), which is a surface glycoprotein that plays a vital role in viral entry. Distinct differences between HA proteins of the virulent and non-virulent strains are seen, especially in the region near residues 68–79 of the HA₂. This region represents the tip of the stalk that is in contact with the receptor chain, HA₁, and therefore likely to provide the greatest effect on the motions of the exposed portion of HA. Comparison of this region between virulent strains (1918 H1N1 and H5N1) and less virulent ones (H3N2 and 1930 H1N1) reveals that predicted disorder can be seen at this region among the more virulent strains and subtypes but is remarkably absent among the distinctly less virulent ones.

Conclusion

The motions created by disorder at crucial regions are likely to impair recognition by immunological molecules and increase the virulence of both the H5N1 and the 1918 H1N1 viruses. The results help explain many puzzling features of the H5N1 and the 1918 H1N1 viruses. Summarizing, HA (and especially its intrinsically disordered regions) can serve as a predictor of the influenza A virulence, even though there may be other proteins that contribute to or exacerbate the virulence.