The hepatitis E virus polyproline region is involved in viral adaptation.
The hepatitis E virus polyproline region is involved in viral adaptation.
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DOI：
10.1371/journal.pone.0035974
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Khudyakov YE
中科院分区：
文献类型：
--
作者：
Purdy MA;Lara J;Khudyakov YE
戊型肝炎病毒（HEV）、风疹病毒和割喉病毒（CTV）基因组中含有一个高脯氨酸密度和低氨基酸复杂性的区域，称为聚脯氨酸区（PPR）。在HEV基因型1、3和4中，它是非结构开放阅读框（ORF 1）内具有正选择（dN/dS>1的4-10个密码子）的唯一区域。该区域具有同源性值>0.5的位点的最高密度。基因型3和4显示PPR中的同源性密度（HD）比ORF 1中的任何其他区域增加了103倍，基因型1没有表现出显著的HD（p<0.0001）。PPR序列的分歧被认为是2倍以上的HEV基因型3和4比基因型1。这些数据表明PPR在宿主范围适应中起着重要作用。虽然PPR似乎是高变和同源的，它保留了尽可能多的系统发育信号的任何其他类似大小的区域在ORF 1，表明趋同进化的主要HEV系统发育谱系内运作。基于序列的二级结构和三级结构的分析确定PPR作为一个内在无序区（IDR），暗示其在复制调控中的作用。所确定的无序到有序状态转换的倾向表明PPR参与蛋白质-蛋白质相互作用。此外，所有四种HEV基因型的PPR包含七个假定的线性结合基序，用于参与调节大量细胞信号传导过程的配体。对这些基序可能的分子功能的基于结构的分析表明，PPR倾向于结合多种配体。总的来说，这些数据表明，在戊型肝炎适应的PPR的作用。特别是作为IDR，PPR可能有助于通过蛋白质-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。
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.
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