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.
J Genet Eng Biotechnol. 2021 Oct 12;19(1):154. doi: 10.1186/s43141-021-00238-8.
Hepatitis E is a liver disease caused by the pathogen hepatitis E virus (HEV). The largest polyprotein open reading frame 1 (ORF1) contains a nonstructural Y-domain region (YDR) whose activity in HEV adaptation remains uncharted. The specific role of disordered regions in several nonstructural proteins has been demonstrated to participate in the multiplication and multiple regulatory functions of the viruses. Thus, intrinsic disorder of YDR including its structural and functional annotation was comprehensively studied by exploiting computational methodologies to delineate its role in viral adaptation.
Based on our findings, it was evident that YDR contains significantly higher levels of ordered regions with less prevalence of disordered residues. Sequence-based analysis of YDR revealed it as a "dual personality" (DP) protein due to the presence of both structured and unstructured (intrinsically disordered) regions. The evolution of YDR was shaped by pressures that lead towards predominance of both disordered and regularly folded amino acids (Ala, Arg, Gly, Ile, Leu, Phe, Pro, Ser, Tyr, Val). Additionally, the predominance of characteristic DP residues (Thr, Arg, Gly, and Pro) further showed the order as well as disorder characteristic possessed by YDR. The intrinsic disorder propensity analysis of YDR revealed it as a moderately disordered protein. All the YDR sequences consisted of molecular recognition features (MoRFs), i.e., intrinsic disorder-based protein-protein interaction (PPI) sites, in addition to several nucleotide-binding sites. Thus, the presence of molecular recognition (PPI, RNA binding, and DNA binding) signifies the YDR's interaction with specific partners, host membranes leading to further viral infection. The presence of various disordered-based phosphorylation sites further signifies the role of YDR in various biological processes. Furthermore, functional annotation of YDR revealed it as a multifunctional-associated protein, due to its susceptibility in binding to a wide range of ligands and involvement in various catalytic activities.
As DP are targets for regulation, thus, YDR contributes to cellular signaling processes through PPIs. As YDR is incompletely understood, therefore, our data on disorder-based function could help in better understanding its associated functions. Collectively, our novel data from this comprehensive investigation is the first attempt to delineate YDR role in the regulation and pathogenesis of HEV.
戊型肝炎是由戊型肝炎病毒（HEV）病原体引起的肝脏疾病。最大的多蛋白开放阅读框1（ORF1）包含一个非结构Y结构域区域（YDR），其在HEV适应性中的活性尚不清楚。已证明几种非结构蛋白中无序区域的特定作用参与病毒的增殖和多种调节功能。因此，通过利用计算方法全面研究了YDR的内在无序性，包括其结构和功能注释，以阐明其在病毒适应性中的作用。
根据我们的研究结果，很明显YDR包含明显更高水平的有序区域，无序残基的发生率较低。基于序列的YDR分析表明，由于存在结构化和非结构化（内在无序）区域，它是一种“双重性格”（DP）蛋白。YDR的进化受到导致无序和规则折叠氨基酸（丙氨酸、精氨酸、甘氨酸、异亮氨酸、亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、酪氨酸、缬氨酸）占主导地位的压力的影响。此外，特征性DP残基（苏氨酸、精氨酸、甘氨酸和脯氨酸）的优势进一步显示了YDR所具有的有序和无序特征。YDR 的内在无序倾向分析表明它是一种中度无序的蛋白。所有YDR序列除了几个核苷酸结合位点外，还由分子识别特征（MoRFs）组成，即基于内在无序的蛋白质-蛋白质相互作用（PPI）位点。因此，分子识别（PPI、RNA结合和DNA结合）的存在表明YDR与特定伙伴、宿主膜的相互作用导致进一步的病毒感染。各种基于无序的磷酸化位点的存在进一步表明YDR在各种生物学过程中的作用。此外，YDR的功能注释表明它是一种多功能相关蛋白，因为它易于与多种配体结合并参与各种催化活性。
由于DP是调节的靶点，因此YDR通过PPI促进细胞信号传导过程。由于对YDR的了解不完全，因此，我们基于无序的功能数据可能有助于更好地理解其相关功能。总的来说，我们从这项全面研究中获得的新数据是首次尝试阐明YDR在HEV调节和发病机制中的作用。
