All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer.
All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer.
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DOI：
10.7554/elife.76356
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发表时间：
2022-06-16
期刊：
影响因子：
7.7
通讯作者：
Lin, Milo M.
中科院分区：
文献类型：
--
作者：
Rizo, Josep;Sari, Levent;Qi, Yife;Im, Wonpil;Lin, Milo M.
关键词：
突触囊泡被引导进入一种状态，即在Ca 2+结合到突触结合蛋白-1时准备好快速释放神经递质。这种状态可能包括囊泡和质膜之间与突触结合蛋白-1和复合蛋白结合的反式陷阱复合物。然而，这种状态的性质和导致膜融合的步骤尚不清楚，部分原因是实验研究这种动态过程的困难。为了阐明这些问题，我们进行了全原子分子动力学模拟的系统包含trans-SNARE复合物之间的两个平面双层或囊泡和一个平面双层有或没有片段的突触结合蛋白-1和/或复合蛋白-1。我们的研究结果需要谨慎解释，因为有限的模拟时间和关键成分的情况下，但建议的机制功能，可以控制释放，并帮助可视化的潜在状态的引发Synaptotagmin-1-SNARE-complexin-1复合物。模拟结果表明，SNARE单独诱导形成扩展的膜-膜接触界面，可能会慢慢融合，并引发状态包含反式SNARE复合物的大分子组件结合到突触结合蛋白-1 C2B结构域和复合蛋白-1弹簧加载的配置，防止过早的膜合并和扩展界面的形成，但保持系统准备快速融合后，Ca 2+流入。
Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to Synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of Synaptotagmin-1 and/or complexin-1. Our results need to be interpreted with caution because of the limited simulation times and the absence of key components, but suggest mechanistic features that may control release and help visualize potential states of the primed Synaptotagmin-1-SNARE-complexin-1 complex. The simulations suggest that SNAREs alone induce formation of extended membrane-membrane contact interfaces that may fuse slowly, and that the primed state contains macromolecular assemblies of trans-SNARE complexes bound to the Synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane merger and formation of extended interfaces, but keeps the system ready for fast fusion upon Ca2+ influx.