PDF(Pubmed)
Abstract：
The SNAP receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus, and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers, and C-terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semirigid rods, squeezing the membranes together as they assemble (\"zipper\") from the N to the C termini. However, the mechanism underlying fast SNARE-induced membrane fusion remains unknown. We have used all-atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemical basis, emphasizes local molecular events over general membrane properties, and explains extensive experimental data. In this model, the central event that initiates fast (microsecond scale) membrane fusion occurs when the SNARE helices zipper into the juxtamembrane linkers which, together with the adjacent transmembrane regions, promote encounters of acyl chains from both bilayers at the polar interface. The resulting hydrophobic nucleus rapidly expands into stalk-like structures that gradually progress to form a fusion pore, aided by the SNARE transmembrane regions and without clearly discernible intermediates. The propensity of polyunsaturated lipids to participate in encounters that initiate fusion suggests that these lipids may be important for the high speed of neurotransmitter release.
摘要：
SNAP受体（SNARE）蛋白syntaxin-1，SNAP-25和突触蛋白通过形成紧密的SNARE复合物来介导神经递质的释放，该复合物在微秒内将突触小泡与质膜融合。膜融合通常通过蛋白质对宏观膜特性的作用来解释，例如曲率，弹性模量,和紧张，一个广泛的模型设想了SNARE的主题，近膜接头，和C-末端跨膜区的突触短蛋白和syntaxin-1形成连续的螺旋，机械地起半刚性棒的作用，将膜从N端组装到C端（“拉链”）时挤压在一起。然而,快速SNARE诱导的膜融合的潜在机制仍然未知。我们已经使用全原子分子动力学模拟来研究这种机制。我们的结果需要谨慎解释，因为模拟的数量和长度有限，但是他们提出了一种具有天然物理化学基础的膜融合模型，强调局部分子事件而不是一般膜性质，并解释了大量的实验数据。在这个模型中,启动快速（微秒级）膜融合的中心事件发生时，SNARE螺旋拉链进入近膜接头，连同相邻的跨膜区，促进来自两个双层的酰基链在极性界面的相遇。产生的疏水性核迅速膨胀成茎状结构，逐渐发展形成融合孔，由SNARE跨膜区域辅助，没有明显可辨别的中间体。多不饱和脂质参与引发融合的相遇的倾向表明，这些脂质对于神经递质的高速释放可能很重要。
