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首页> 外文期刊>Journal of Molecular Biology >Fatty acids can substitute the HIV fusion peptide in lipid merging and fusion: An analogy between viral and palmitoylated eukaryotic fusion proteins
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Fatty acids can substitute the HIV fusion peptide in lipid merging and fusion: An analogy between viral and palmitoylated eukaryotic fusion proteins

机译：脂肪酸可以在脂质融合和融合中替代HIV融合肽：病毒和棕榈酰化的真核融合蛋白之间的类比

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Various fusion proteins from eukaryotes and viruses share structural similarities such as a coiled coil motif. However, compared with eukaryotic proteins, a viral fusion protein contains a fusion pepticle (FP), which is an N-terminal hydrophobic fragment that is primarily involved in directing fusion via anchoring the protein to the target cell membrane. In various eukaryotic fusion proteins the membrane targeting domain is cysteine-rich and must undergo palmitoylation prior to the fusion process. Here we examined whether fatty acids can replace the FP of human immunodeficiency virus type 1 (HIV-1), thereby discerning between the contributions of the sequence versus hydrophobicity of the FP in the lipid-merging process. For that purpose, we structurally and functionally characterized peptides derived from the N terminus of HIV fusion protein - gp41 in which the FP is lacking or replaced by fatty acids. We found that fatty acid conjugation dramatically enhanced the capability of the peptides to induce lipid mixing and aggregation of zwitterionic phospholipids composing the outer leaflet of eukaryotic cell membranes. The enhanced effect of the acylated peptides on membranes was further supported by real-time atomic force microscopy (AFM) showing nanoscale holes in zwitterionic membranes. Membrane-binding experiments revealed that fatty acid conjugation did not increase the affinity of the peptides to the membrane significantly. Furthermore, all free and acylated peptides exhibited similar alpha-helical structures in solution and in zwitterionic membranes. Interestingly, the fusogenic active conformation of N36 in negatively charged membranes composing the inner leaflet of eukaryotic cells is beta-sheet. Apparently, N-terminal heptad repeat (NHR) can change its conformation as a response to a change in the charge of the membrane head group. Overall, the data suggest an analogy between the eukaryotic cysteine-rich domains and the viral fusion peptide, and mark the hydrophobic nature of FP as an important characteristic for its role in lipid merging. (c) 2007 Elsevier Ltd. All rights reserved.
机译：来自真核生物和病毒的各种融合蛋白具有相似的结构，例如卷曲的螺旋基序。但是，与真核蛋白相比，病毒融合蛋白包含融合消化物（FP），它是一个N端疏水片段，主要通过将蛋白锚定在靶细胞膜上来参与融合。在各种真核融合蛋白中，膜靶向结构域富含半胱氨酸，并且必须在融合过程之前进行棕榈酰化。在这里，我们检查了脂肪酸是否可以替代人类免疫缺陷病毒1型（HIV-1）的FP，从而在脂质合并过程中区分了FP的序列与疏水性之间的关系。为此，我们在结构和功能上表征了源自HIV融合蛋白-gp41 N末端的肽，其中FP缺乏或被脂肪酸取代。我们发现，脂肪酸结合显着增强了肽诱导脂质混合和组成真核细胞膜外小叶的两性离子磷脂聚集的能力。实时原子力显微镜（AFM）进一步显示了酰化肽对膜的增强作用，该结果显示了两性离子膜中的纳米级孔。膜结合实验表明，脂肪酸结合不会显着增加肽与膜的亲和力。此外，所有游离和酰化的肽在溶液和两性离子膜中均表现出相似的α-螺旋结构。有趣的是，组成真核细胞内小叶的带负电荷的膜中N36的融合活性构象是β-折叠。显然，N端七肽重复序列（NHR）可以改变其构象，作为对膜头基团电荷变化的响应。总体而言，数据表明在真核生物富含半胱氨酸的结构域和病毒融合肽之间存在类比，并标志着FP的疏水性是其在脂质融合中的重要特征。 （c）2007 Elsevier Ltd.保留所有权利。

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