the hepatitis e virus polyproline region is involved in viral adaptation戊肝病毒polyproline地区参与病毒适应.pdfVIP

The Hepatitis E Virus Polyproline Region Is Involved in Viral Adaptation Michael A. Purdy*, James Lara, Yury E. Khudyakov Centers for Disease Control and Prevention, National Center for HIV/Hepatitis/STD/TB Prevention, Division of Viral Hepatitis, Atlanta, Georgia, United States of America Abstract Genomes of hepatitis E virus (HEV), rubivirus and cutthroat virus (CTV) contain a region of high proline density and low amino acid (aa) complexity, named the polyproline region (PPR). In HEV genotypes 1, 3 and 4, it is the only region within the non-structural open reading frame (ORF1) with positive selection (4–10 codons with dN/dS.1). This region has the highest density of sites with homoplasy values .0.5. Genotypes 3 and 4 show ,3-fold increase in homoplastic density (HD) in the PPR compared to any other region in ORF1, genotype 1 does not exhibit significant HD (p,0.0001). PPR sequence divergence was found to be 2-fold greater for HEV genotypes 3 and 4 than for genotype 1. The data suggest the PPR plays an important role in host-range adaptation. Although the PPR appears to be hypervariable and homoplastic, it retains as much phylogenetic signal as any other similar sized region in the ORF1, indicating that convergent evolution operates within the major HEV phylogenetic lineages. Analyses of sequence-based secondary structure and the tertiary structure identify PPR as an intrinsically disordered region (IDR), implicating its role in regulation of replication. The identified propensity for the disorder-to-order state transitions indicates the PPR is involved in protein-protein interactions. Furthermore, the PPR of all four HEV genotypes contains seven putative linear binding