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 motifs for ligands involved in the regulation of a wide number of cellular signaling processes. Structure-based analysis of possible molecular functions of these motifs showed the PPR is prone to bind a wide variety of ligands. Collectively, these data suggest a role for the PPR in HEV adaptation. Particularly as an IDR, the PPR likely contributes to fine tuning of viral replication through protein-protein interactions and should be considered as a target for development of novel anti-viral drugs.
Highlights
Hepatitis E virus (HEV), a hepevirus [1], causes epidemic and sporadic cases of hepatitis in humans [2]
Proline distribution within the ORF1-protein The ORF1-encoded proteins of hepeviruses were examined using a Perl script to count the number of Pro residues within a 30aa sliding window
An alignment of HEV genotype 1–4 sequences showed that the polyproline region (PPR) was bound by conserved sequences TLYTRTWS and RRLLXTYPDG at the N- and C-sides, respectively
Summary
Hepatitis E virus (HEV), a hepevirus [1], causes epidemic and sporadic cases of hepatitis in humans [2]. HEV infection and hepatitis E were encountered primarily in developing countries, and in developed countries were recognized as associated with international travel. As detection techniques have improved, HEV infection has been found to be more prevalent than originally thought and is currently found worldwide [3]. HEV sequences are segregated into four genotypes. HEV genotypes 1 and 2 infect primarily humans along the fecal/ oral transmission route, while genotypes 3 and 4 can infect humans, swine, deer and boar. Infection by genotypes 3 and 4 appears to be primarily zoonotic [4,5]. The epidemiology of HEV infections is complex and the virus can be transmitted through multiple modes [6]
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