Shafat Zoya, Ahmed Anwar, Parvez Mohammad K, Parveen Shama
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Centre of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia.
Bioinformation. 2021 Sep 30;17(9):818-828. doi: 10.6026/97320630017818. eCollection 2021.
Hepatitis E virus (HEV) is the main cause of acute hepatitis worldwide. HEV accounts for up to 30% mortality rate in pregnant women, with highest incidences reported for genotype 1 (G1) HEV. The contributing factors in adverse cases during pregnancy in women due to HEV infection is still debated. The mechanism underlying the pathogenesis of viral infection is attributed to different genomic component of HEV, i.e., open reading frames (ORFs): ORF1, ORF2, ORF3 and ORF4. Recently, ORF4 has been discovered in enhancing the replication of GI isolates of HEV through regulation of an IRES-like RNA element. However, its characterization through computational methodologies remains unexplored. In this novel study, we provide comprehensive overview of ORF4 protein's genetic and molecular characteristics through analyzing its sequence and different structural levels. A total of three different datasets (Human, Rat and Ferret) of ORF4 genomes were built and comparatively analyzed. Several non-synonymous mutations in conjunction with higher entropy values were observed in rat and ferret datasets, however, limited variation was observed in human ORF4 genomes. Higher transition to tranversion ratio was observed in the ORF4 genomes. Studies have reported the association of intrinsic disordered proteins (IDP) with drug discovery due to its role in several signaling and regulatory processes through protein-protein interactions (PPIs). As PPIs are potent drug target sources, thus the ORF4 protein was explored by analyzing its polypeptide structure in order to shed light on its intrinsic disorder. Pressures that lead towards preponderance of disordered-promoting amino acid residues shaped the evolution of ORF4. The intrinsic disorder propensity analysis revealed ORF4 protein (Human) as a highly disordered protein (IDP). Predominance of coils and lack of secondary structure further substantiated our findings suggesting its involvement in binding to ligand molecules. Thus, ORF4 contributes to cellular signaling processes through protein-protein interactions, as IDPs are targets for regulation to accelerate the process of drug designing strategies against HEV infections.
戊型肝炎病毒（HEV）是全球急性肝炎的主要病因。HEV在孕妇中的死亡率高达30%，其中基因型1（G1）HEV的发病率最高。HEV感染导致孕妇不良病例的相关因素仍存在争议。病毒感染发病机制的基础归因于HEV的不同基因组成分，即开放阅读框（ORF）：ORF1、ORF2、ORF3和ORF4。最近，人们发现ORF4通过调节一种类似内部核糖体进入位点（IRES）的RNA元件来增强HEV基因1型分离株的复制。然而，通过计算方法对其特征的研究仍未开展。在这项新研究中，我们通过分析其序列和不同结构水平，全面概述了ORF4蛋白的遗传和分子特征。共构建了三个不同的ORF4基因组数据集（人类、大鼠和雪貂）并进行了比较分析。在大鼠和雪貂数据集中观察到了一些非同义突变以及较高的熵值，然而，人类ORF4基因组中的变异有限。在ORF4基因组中观察到较高的转换与颠换比率。研究报告称，内在无序蛋白（IDP）因其通过蛋白质-蛋白质相互作用（PPI）在多种信号传导和调节过程中的作用，与药物发现相关。由于PPI是有效的药物靶点来源，因此通过分析ORF4蛋白的多肽结构来探索该蛋白，以阐明其内在无序性。导致促进无序的氨基酸残基占优势的压力塑造了ORF4的进化。内在无序倾向分析显示ORF4蛋白（人类）是一种高度无序的蛋白（IDP）。卷曲结构的优势和二级结构的缺乏进一步证实了我们的发现，表明它参与与配体分子的结合。因此，ORF4通过蛋白质-蛋白质相互作用促进细胞信号传导过程，因为IDP是调节靶点，可加速针对HEV感染的药物设计策略进程。
