Fletcher Sean, Biswas-Fiss Esther E, Biswas Subhasis B
Department of Medical and Molecular Sciences, College of Health Sciences, University of Delaware, Newark, DE, 19716, USA.
Virol J. 2025 Aug 13;22(1):278. doi: 10.1186/s12985-025-02903-7.
Human papillomavirus (HPV) is a prevalent viral pathogen that causes a variety of malignancies, including cervical cancer, one of the leading causes of cancer-related deaths among women worldwide. The HPV E2 protein is a central regulator of viral replication and oncogene expression, making it a critical determinant of HPV-associated malignancies. While its core functions are conserved, variations within the E2 protein are thought to contribute to the differential oncogenic potential among HPV types, though the structural basis for this remains incompletely understood. Previous research from our laboratory suggests that mutations within a 12-base pair segment of the long control region that encompasses the E2 binding sites may influence the oncogenic potential of certain HPV strains.
Computational methods, including multiple sequence alignment, phylogenetic analysis, and protein structural modeling were employed to identify conserved regions and correlate these with potential cancer-associated mutations in the coding region.
Structural modeling using AlphaFold3 and visualization in PyMOL revealed that conserved E2 residues cluster near the DNA-binding surface in the C-terminal domain and at critical interaction sites in the N-terminal transactivation domain, important for E1 DNA helicase binding and potentially other host factor interactions. Notably, species-specific adaptations, including the T309P substitution in the HPV52 subfamily B2, which may induce structural changes in the DNA-binding domain, and variations in the 12-base pair spacer, could modulate oncogene expression.
Collectively, these findings refine our understanding of E2's essential role in viral pathogenesis and highlight promising targets for therapeutic intervention in high-risk HPV strains.
人乳头瘤病毒（HPV）是一种常见的病毒病原体，可引发多种恶性肿瘤，包括宫颈癌，而宫颈癌是全球女性癌症相关死亡的主要原因之一。HPV E2蛋白是病毒复制和癌基因表达的核心调节因子，是HPV相关恶性肿瘤的关键决定因素。虽然其核心功能是保守的，但E2蛋白内的变异被认为会导致不同HPV类型之间致癌潜力的差异，不过其结构基础仍未完全明确。我们实验室之前的研究表明，包含E2结合位点的长控制区12个碱基对片段内的突变可能会影响某些HPV毒株的致癌潜力。
采用多种计算方法，包括多序列比对、系统发育分析和蛋白质结构建模，以识别保守区域，并将这些区域与编码区潜在的癌症相关突变相关联。
使用AlphaFold3进行的结构建模以及在PyMOL中的可视化显示，保守的E2残基聚集在C端结构域的DNA结合表面附近以及N端反式激活结构域的关键相互作用位点，这对于E1 DNA解旋酶结合以及潜在的其他宿主因子相互作用很重要。值得注意的是，物种特异性适应性变化，包括HPV52 B2亚家族中的T309P替代，这可能会诱导DNA结合结构域的结构变化，以及12个碱基对间隔区的变异，可能会调节癌基因表达。
总体而言，这些发现完善了我们对E2在病毒发病机制中重要作用的理解，并突出了针对高危HPV毒株进行治疗干预的有前景的靶点。
