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


CONCLUSIONS
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.
Goh
Gerard Kian-Meng
GK
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. gerard@compbio.iupui.edu
Dunker
A Keith
AK
Uversky
Vladimir N
VN
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006389:Hemagglutinins, Viral / Q000737:chemistry*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000472:pathogenicity*; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry / Q000472:pathogenicity; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000821:virology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014774:Virulence
D006389:Hemagglutinins, Viral; C458881:hemagglutinin fusogenic peptide, influenza virus