In silico prediction of structural changes in human papillomavirus type 16 (HPV16) E6 oncoprotein and its variants
In silico prediction of structural changes in human papillomavirus type 16 (HPV16) E6 oncoprotein and its variants
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DOI：
10.1186/s12860-019-0217-0
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发表时间：
2019-08-19
影响因子：
2.8
通讯作者：
Antonio Leyva-Vazquez, Marco
中科院分区：
文献类型：
--
作者：
Alberto Rodriguez-Ruiz, Hugo;Lilia Garibay-Cerdenares, Olga;Antonio Leyva-Vazquez, Marco
背景HPV 16感染是宫颈癌发生的主要危险因素之一，主要是由于病毒蛋白E6和E7的高致癌潜力，它们参与了不同的恶性转化过程。E6的非典型内变异具有广泛的谱，这反映在其高度多样性、生物学行为、全球分布和导致宫颈癌的风险上。实验研究表明，来自欧洲变体（E-G350、E-A176/G350、E-C188/G350）和亚洲-美国变体（AAa和AAc）的蛋白E6的非典型内变体能够诱导参与宫颈癌发展的基因的差异表达。结果使用HPV 16 E6癌蛋白（PDB：4XR 8; H链）的结构作为模板，进行计算机分析以表征这些变化的分子效应。特别是，我们通过结构比对，ERRAT，Ramachandran图和蛋白质紊乱预测评估了非典型变异体的3D结构，并通过分子动力学模拟进一步验证了这一点。总的来说，我们的结果显示蛋白质3D结构没有显著变化。然而，我们观察到蛋白质的理化特性和结构紊乱的N-和C-末端的微妙变化。结论HPV 16型6种高危变异株的E6基因突变均为中性突变，除轻微的结构紊乱外，未引起明显的结构改变。由于结构紊乱涉及蛋白质-蛋白质相互作用的重新布线，这些结果表明E6与靶蛋白P53的相互作用的差异模式，以及与E6癌蛋白的某些类型的变体相关的肿瘤侵袭性的可能不同模式。
Background HPV16 infection is one of the main risk factors involved in the development of cervical cancer, mainly due to the high oncogenic potential of the viral proteins E6 and E7, which are involved in the different processes of malignant transformation. There is a broad spectrum of intratypical variation of E6, which is reflected in its high diversity, biological behavior, global distribution and risk of causing cervical cancer. Experimental studies have shown that the intratypical variants of the protein E6 from the European variants (E-G350, E-A176/G350, E-C188/G350) and Asian-American variants (AAa and AAc), are capable of inducing the differential expression of genes involved in the development of cervical cancer. Results An in silico analysis was performed to characterize the molecular effects of these variations using the structure of the HPV16 E6 oncoprotein (PDB: 4XR8; chain H) as a template. In particular, we evaluated the 3D structures of the intratypical variants by structural alignment, ERRAT, Ramachandran plots and prediction of protein disorder, which was further validated by molecular dynamics simulations. Our results, in general, showed no significant changes in the protein 3D structure. However, we observed subtle changes in protein physicochemical features and structural disorder in the N- and C-termini. Conclusions Our results showed that mutations in the viral oncogene E6 of six high-risk HPV16 variants are effectively neutral and do not cause significant structural changes except slight variations of structural disorder. As structural disorder is involved in rewiring protein-protein interactions, these results suggest a differential pattern of interaction of E6 with the target protein P53 and possibly different patterns of tumor aggressiveness associated with certain types of variants of the E6 oncoprotein.