Bentz J, Mittal A
Department of Bioscience and Biotechnology, Drexel University, Philadelphia, PA 19104, USA.
Cell Biol Int. 2000;24(11):819-38. doi: 10.1006/cbir.2000.0632.
It is clear that both viral and intracellular membrane fusion proteins contain a minimal set of domains which must be deployed at the appropriate time during the fusion process. An account of these domains and their functions is given here for the four best-described fusion systems: influenza HA, sendai virus F1, HIV gp120/41 and the neuronal SNARE core composed of synaptobrevin (syn), syntaxin (stx) and the N- and C-termini of SNAP25 (sn25), together with the Ca(2+)binding protein synaptotagmin (syt). Membrane fusion begins with the binding of the virion or vesicle to the target membrane via receptors. The committed step in influenza HA- mediated fusion begins with an aggregate of HAs (at least eight) with some of their HA2 N-termini, a.k.a. fusion peptides, embedded into the viral bilayer (Bentz, 2000 a). The hypothesis presented in Bentz (2000 b) is that the conformational change of HA to the extended coiled coil extracts the fusion peptides from the viral bilayer. When this extraction occurs from the center of the site of restricted lipid flow, it exposes acyl chains and parts of the HA transmembrane domains to the aqueous media, i.e. a hydrophobic defect is formed. This is the 'transition state' of the committed step of fusion. It is stabilized by a 'dam' of HAs, which are inhibited from diffusing away by the rest of the HAs in the aggregate and because that would initially expose more acyl chains to water. Recruitment of lipids from the apposed target membrane can heal this hydrophobic defect, initiating lipid mixing and fusion. The HA transmembrane domains are required to be part of the hydrophobic defect, because the HA aggregate must be closely packed enough to restrict lipid flow. This hypothesis provides a simple and direct coupling between the energy released by the formation of the coiled coil to the energy needed to create and stabilize the high energy intermediates of fusion. Several of these essential domains have been described for the viral fusion proteins SV5 F1 and HIV gp120/41, and for the intracellular SNARE fusion system. By comparing these domains, we have constructed a minimal set which appears to be adequate to explain how the conformational changes can produce a successful fusion event, i.e. communication of aqueous compartments.
很明显，病毒和细胞内膜融合蛋白都包含一组最小的结构域，这些结构域必须在融合过程中的适当时间发挥作用。本文介绍了四个描述得最为详尽的融合系统中这些结构域及其功能：流感病毒血凝素（HA）、仙台病毒F1、HIV gp120/41以及由突触小泡蛋白（syn）、 syntaxin（stx）和SNAP25（sn25）的N端和C端组成的神经元SNARE核心，以及Ca(2+)结合蛋白突触结合蛋白（syt）。膜融合始于病毒粒子或囊泡通过受体与靶膜结合。流感病毒HA介导的融合中的关键步骤始于HA（至少八个）聚集体，其一些HA2 N端，即融合肽，嵌入病毒双层膜中（Bentz，2000a）。Bentz（2000b）提出的假说是，HA向延伸的卷曲螺旋的构象变化将融合肽从病毒双层膜中提取出来。当这种提取发生在脂质流动受限部位的中心时，它会将酰基链和HA跨膜结构域的部分暴露于水性介质中，即形成疏水缺陷。这是融合关键步骤的“过渡态”。它由HA的“屏障”稳定，HA聚集体中的其他HA阻止其扩散，因为这最初会使更多酰基链暴露于水中。从相邻靶膜募集脂质可以修复这种疏水缺陷，启动脂质混合和融合。HA跨膜结构域必须是疏水缺陷的一部分，因为HA聚集体必须紧密堆积以限制脂质流动。该假说提供了卷曲螺旋形成所释放的能量与创建和稳定融合的高能中间体所需能量之间简单而直接的耦合。这些基本结构域中的几个已在病毒融合蛋白SV5 F1和HIV gp120/41以及细胞内SNARE融合系统中得到描述。通过比较这些结构域，我们构建了一组最小的结构域，似乎足以解释构象变化如何产生成功的融合事件，即水性区室的连通。
