A strong correlation between fusogenicity and membrane insertion depth of the HIV fusion peptide
A strong correlation between fusogenicity and membrane insertion depth of the HIV fusion peptide
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DOI：
10.1073/pnas.0907360106
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发表时间：
2009-09-08
影响因子：
11.1
通讯作者：
Weliky, David P.
中科院分区：
文献类型：
--
作者：
Qiang, Wei;Sun, Yan;Weliky, David P.
HIV的膜与宿主细胞的膜之间的融合是HIV感染中的关键步骤，并且通过HIV gp 41蛋白的融合肽结构域（HFP）与宿主细胞膜的结合来催化。HFP本身诱导囊泡融合，并且是理解融合肽/宿主细胞膜相互作用的有用模型系统。本文报道了不同HFP构建体的膜位置与其融合性之间的实验相关性。构建体是具有瓦尔-2至Glu-2突变的HFP单体（HFPmn_mut）、野生型HFP单体（HFPmn）和野生型HFP三聚体（HFPtr）。所有构建体在具有生理学相关胆固醇含量的膜中具有主要的β折叠结构。HFPmn_mut不融合囊泡，HFPmn具有中等融合速率，HFPtr具有HIV gp 41的推定寡聚化状态和非常快的融合速率。用固态NMR测量HFP骨架中标记的羰基（（CO）-C-13）核与膜双层的表面或内部区域中的脂质核之间的距离来探测HFP膜位置。HFPmn_mut位于膜表面，HFPmn插入单个膜小叶中，HFPtr是与膜中心接触的插入最深的结构。这些结果显示了HFP构建体的插入深度和融合活性之间的明显正相关性。其他致病包膜病毒含有融合肽，这种相关性可能是这些肽的一般结构-功能模型。
Fusion between the membrane of HIV and the membrane of a host cell is a crucial step in HIV infection and is catalyzed by the binding of the fusion peptide domain (HFP) of the HIV gp41 protein to the host cell membrane. The HFP by itself induces vesicle fusion and is a useful model system to understand the fusion peptide/host cell membrane interaction. This article reports an experimental correlation between the membrane locations of different HFP constructs and their fusogenicities. The constructs were the HFP monomer with Val-2 to Glu-2 mutation (HFPmn_mut), wild type HFP monomer (HFPmn), and wild type HFP trimer (HFPtr). All constructs have predominant beta sheet structure in membranes with physiologically relevant cholesterol content. HFPmn_mut does not fuse vesicles, HFPmn has moderate fusion rate, and HFPtr has the putative oligomerization state of HIV gp41 and a very rapid fusion rate. The HFP membrane locations were probed with solid-state NMR measurements of distances between labeled carbonyl ((CO)-C-13) nuclei in the HFP backbone and lipid nuclei in the surface or interior regions of the membrane bilayer. HFPmn_mut is located at the membrane surface, HFPmn is inserted into a single membrane leaflet, and HFPtr is the most deeply inserted construct with contact with the center of the membrane. These results show a clear positive correlation between the insertion depths and the fusion activities of the HFP constructs. Other disease-causing enveloped viruses contain fusion peptides and this correlation may be a general structure-function model for these peptides.