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pH-dependent conformational change within the Lassa virus transmembrane domain elicits efficient membrane fusion
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 2.8 ) Pub Date : 2023-09-19 , DOI: 10.1016/j.bbamem.2023.184233
Patrick M Keating 1 , Nicholas P Schifano 1 , Xinrui Wei 1 , Matthew Y Kong 1 , Jinwoo Lee 1
Affiliation  

Lassa virus (LASV) is the most prevalent member of the arenavirus family and the causative agent of Lassa fever, a viral hemorrhagic fever. Although there are annual outbreaks in West Africa, and recently isolated cases worldwide, there are no current therapeutics or vaccines, which poses LASV as a significant global public health threat. One of the key steps in LASV infection is the delivery of its genetic material by fusing its viral membrane with the host cell membrane. This process is facilitated by significant conformational changes within glycoprotein 2 (GP2), yielding distinct prefusion and postfusion structural states. However, structural information is missing to understand the changes that occur in the transmembrane domain during the fusion process. Here, we used CD and NMR spectroscopy to show that the transmembrane domain has pH-dependent conformational changes that result in an extension of the alpha helix at the N-terminal end. Proline mutants of key residues in that region prevent the helical extension, as seen in CD and NMR. We developed a modified lipid mixing assay to study the importance of this extension on the function of GP2. Our assay shows that membrane fusion efficiency is optimal at low pH values but introducing the proline mutants results in lower fusion efficiency. These results indicate that these pH-dependent conformational changes are important to the fusion mechanism. This information can be used to design therapeutics to combat Lassa virus infections and prevent its potential spread.



中文翻译:

拉沙病毒跨膜域内 pH 依赖性构象变化引发有效的膜融合

拉沙病毒(LASV) 是沙粒病毒家族中最流行的成员,也是拉沙热(一种病毒性出血热)的病原体。尽管西非每年都会爆发,并且最近在世界各地都有孤立的病例,但目前尚无治疗方法或疫苗,这使 LASV 成为一个重大的全球公共卫生威胁。LASV 感染的关键步骤之一是通过将病毒膜与宿主细胞膜融合来传递其遗传物质。糖蛋白 2 (GP2) 内显着的构象变化促进了这一过程,产生不同的融合前和融合后结构状态。然而,缺少结构信息来理解融合过程中跨膜域发生的变化。在这里,我们使用CD和 NMR 光谱表明跨膜结构域具有 pH 依赖性构象变化,导致N 末端的α 螺旋该区域关键残基的脯氨酸突变体阻止了螺旋延伸,如 CD 和 NMR 中所示。我们开发了一种改良的脂质混合测定法来研究这种延伸对 GP2 功能的重要性。我们的测定表明,膜融合效率在低 pH 值下最佳,但引入脯氨酸突变体会导致融合效率降低。这些结果表明这些 pH 依赖性构象变化对于融合机制很重要。这些信息可用于设计治疗方法来对抗拉沙病毒感染并防止其潜在传播。

更新日期:2023-09-23
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