Taylor A, O'Leary J M, Pollock S, Zitzmann N
Department of Biochemistry, and Oxford Glycobiology University of Oxford, South Parks Road, Oxford, OX1 3QU.
Protein Pept Lett. 2009;16(7):815-22. doi: 10.2174/092986609788681779.
The mechanism(s) by which hepatitis C virus (HCV) enters and infects cells remains unknown. Identifying the HCV fusion peptide(s) and understanding the early stages of infection may provide new opportunities for improved antiviral therapy. The HCV envelope glycoprotein E2 is thought to be a class II fusion protein. Class II fusion proteins are exemplified by the E protein of the tick-borne encephalitis virus (TBEV) and the E1 protein of the Semliki Forest virus (SFV). Analysis of the hydrophobicity profiles of four HCV E2 envelope glycoproteins revealed a region with a conserved three-pronged pattern of hydrophobicity, termed the tridentate (TD) region. The primary sequence of the TD region is highly conserved in all 490 HCV strains currently reported. The known fusion peptide loops of TBEV and SFV share the characteristic TD region hydrophobicity profile and significant sequence conservation in the TD region was identified in the E and E1 glycoproteins of members of the Flaviviridae and Togaviridae families, respectively. The HCV TD region peptides have membranotropic activity; in molecular dynamics (MD) simulations, the HCV TD region peptides insert into in a biomimetic bilayer in a similar manner to the TBEV fusion peptide and the peptides induce effective mixing of lipid membranes in a liposome fusion assay. Together these results indicate that the highly conserved TD region of the HCV E2 protein is a fusion peptide candidate and may be an important factor in the class II fusion mechanism.
丙型肝炎病毒（HCV）进入并感染细胞的机制尚不清楚。确定HCV融合肽并了解感染的早期阶段可能为改进抗病毒治疗提供新的机会。HCV包膜糖蛋白E2被认为是一种II类融合蛋白。蜱传脑炎病毒（TBEV）的E蛋白和Semliki森林病毒（SFV）的E1蛋白是II类融合蛋白的代表。对四种HCV E2包膜糖蛋白的疏水性图谱分析揭示了一个具有保守三叉状疏水模式的区域，称为三齿状（TD）区域。TD区域的一级序列在目前报道的所有490株HCV毒株中高度保守。TBEV和SFV已知的融合肽环具有TD区域的特征性疏水性图谱，并且分别在黄病毒科和披膜病毒科成员的E和E1糖蛋白中鉴定出TD区域具有显著的序列保守性。HCV TD区域肽具有膜otropic活性；在分子动力学（MD）模拟中，HCV TD区域肽以与TBEV融合肽类似的方式插入仿生双层膜中，并且这些肽在脂质体融合试验中诱导脂质膜的有效混合。这些结果共同表明，HCV E2蛋白高度保守的TD区域是融合肽候选物，可能是II类融合机制中的一个重要因素。
