Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30329, USA.
Nat Commun. 2023 Jan 26;14(1):433. doi: 10.1038/s41467-023-36183-y.
Hepatitis C virus (HCV) uses a hybrid entry mechanism. Current structural data suggest that upon exposure to low pH and Cluster of Differentiation 81 (CD81), the amino terminus of envelope glycoprotein E2 becomes ordered and releases an internal loop with two invariant aromatic residues into the host membrane. Here, we present the structure of an amino-terminally truncated E2 with the membrane binding loop in a bent conformation and the aromatic side chains sequestered. Comparison with three previously reported E2 structures with the same Fab indicates that this internal loop is flexible, and that local context influences the exposure of hydrophobic residues. Biochemical assays show that the amino-terminally truncated E2 lacks the baseline membrane-binding capacity of the E2 ectodomain. Thus, the amino terminal region is a critical determinant for both CD81 and membrane interaction. These results provide new insights into the HCV entry mechanism.
丙型肝炎病毒（HCV）使用混合进入机制。目前的结构数据表明，在接触低 pH 值和分化簇 81（CD81）后，包膜糖蛋白 E2 的氨基末端变得有序，并将带有两个不变芳香族残基的内部环释放到宿主膜中。在这里，我们展示了一个氨基末端截断的 E2 结构，其膜结合环呈弯曲构象，芳香侧链被隔离。与具有相同 Fab 的之前报道的三种 E2 结构的比较表明，该内部环是灵活的，并且局部环境会影响疏水性残基的暴露。生化分析表明，氨基末端截断的 E2 缺乏 E2 胞外域的基线膜结合能力。因此，氨基末端区域是 CD81 和膜相互作用的关键决定因素。这些结果为 HCV 进入机制提供了新的见解。
Nat Commun. 2023-1-26
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