Demonstrating the C-terminal boundary of the HIV 1 fusion conformation in a dynamic ongoing fusion process and implication for fusion inhibition
Demonstrating the C-terminal boundary of the HIV 1 fusion conformation in a dynamic ongoing fusion process and implication for fusion inhibition
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DOI：
10.1096/fj.07-8582com
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发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Shai, Yechiel
中科院分区：
文献类型：
--
作者：
Wexler-Cohen, Yael;Shai, Yechiel
核心复合物是参与许多病毒的融合机制以及细胞内囊泡融合的结构。研究HIV-1-细胞融合的动态阶段的一种强有力的方法是利用DP 178，一种来自病毒已知序列的核心复合物抑制肽。引人注目的是，我们发现脂肪酸可以取代DP 178的整个C-末端区域，已知在肽的活性中起着至关重要的作用。抑制活性与脂肪酸的长度相关，与脂肪酸附着的方向（N-或C-末端）相关，并且如通过新的三重染色测定所设想的，与细胞上的肽的浓度相关。我们的研究结果表明，第一次，C-末端边界的内源性核心结构在原位和建立的C-末端区域的DP 178功能主要是作为一个锚的细胞膜。除了机制的影响，这种短的脂肽提供了新的，有前途的融合抑制剂。由于HIV-1的融合机制与其他病原体-包膜病毒和胞内囊泡融合机制相同，因此我们的研究结果可能会影响这些系统的研究和治疗工作。
The core complex is a structure involved in the fusion mechanism of many viruses, as well as in intracellular vesicle fusion. A powerful approach for studying the dynamic stages of HIV-1-cell fusion utilizes DP178, a core complex inhibitory peptide derived from the known sequence of the virus. Strikingly, we show that fatty acids can replace the entire C-terminal region of DP178, known to play a crucial role in the activity of the peptide. The inhibitory activity correlated with the length of the fatty acid, with the direction of fatty acid attachment (N-or C-terminus) and, as envisioned by a new triple staining assay, with the concentration of the peptides on cells. Our findings indicate, for the first time, the C-terminal boundary of the endogenous core structure in situ and establish that the C-terminal region of DP178 functions mainly as an anchor to the cell membrane. Apart from the mechanistic implications, such short lipopeptides provide new, promising fusion inhibitors. Because the fusion mechanism of HIV-1 is shared by other pathogen-enveloped viruses and by intracellular vesicle fusion, our results might influence the research and therapeutic efforts in these systems as well.