Centers for Disease Control and Prevention, National Center for HIV/Hepatitis/STD/TB Prevention, Division of Viral Hepatitis, Atlanta, Georgia, United States of America.
PLoS One. 2012;7(4):e35974. doi: 10.1371/journal.pone.0035974. Epub 2012 Apr 24.
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.
戊型肝炎病毒（HEV）、风疹病毒和鲑鱼传染性贫血病毒（CTV）的基因组含有一个脯氨酸密度高、氨基酸（aa）复杂度低的区域，称为多脯氨酸区（PPR）。在 HEV 基因型 1、3 和 4 中，它是 ORF1 中唯一具有正选择（4-10 个密码子的 dN/dS>1）的区域。该区域具有最高密度的同源性值>0.5 的位点。与 ORF1 中的任何其他区域相比，基因型 3 和 4 的 PPR 中同源性密度（HD）增加了约 3 倍，而基因型 1 则没有显著的 HD（p<0.0001）。研究发现，HEV 基因型 3 和 4 的 PPR 序列分化是基因型 1 的 2 倍。数据表明，PPR 在宿主范围适应中起着重要作用。尽管 PPR 似乎具有高度可变性和同源性，但它保留了 ORF1 中任何其他类似大小区域的大部分系统发育信号，表明趋同进化在主要的 HEV 系统发育谱系中起作用。基于序列的二级结构和三级结构分析表明，PPR 是一个固有无序区（IDR），暗示其在复制调控中的作用。无序到有序状态转变的倾向表明，PPR 参与了蛋白质-蛋白质相互作用。此外，所有 4 种 HEV 基因型的 PPR 都包含 7 个潜在的线性配体结合基序，这些基序参与了广泛的细胞信号转导过程的调节。对这些基序可能的分子功能的结构分析表明，PPR 易于结合多种配体。综上所述，这些数据表明 PPR 在 HEV 适应中发挥作用。特别是作为一个 IDR，PPR 可能通过蛋白质-蛋白质相互作用对病毒复制进行微调，应被视为开发新型抗病毒药物的靶点。
