Upon Ca2+ influx, synaptic vesicles fuse with the presynaptic plasma membrane (PM) to release neurotransmitters. Membrane fusion is triggered by synaptotagmin-1, a transmembrane protein in the vesicle membrane (VM), but the mechanism is under debate. Synaptotagmin-1 contains a single transmembrane helix (TM) and two tandem C2 domains (C2A and C2B). This study aimed to use molecular dynamics simulations to elucidate how Ca2+-bound synaptotagmin-1, by simultaneously associating with VM and PM, brings them together for fusion. Although C2A stably associates with VM via two Ca2+-binding loops, C2B has a propensity to partially dissociate. Importantly, an acidic motif in the TM-C2A linker competes with VM for interacting with C2B, thereby flipping its orientation to face PM. Subsequently, C2B readily associates with PM via a polybasic cluster and a Ca2+-binding loop. The resulting mechanistic model for the triggering of membrane fusion by synaptotagmin-1 reconciles many experimental observations.

中文翻译：

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Synaptotagmin-1在触发囊泡融合中的膜结合和功能机制

Ca2+ 流入后，突触小泡与突触前质膜 (PM) 融合以释放神经递质。膜融合由突触结合蛋白-1 触发，突触结合蛋白是囊泡膜 (VM) 中的一种跨膜蛋白，但其机制尚有争议。Synaptotagmin-1 包含一个跨膜螺旋 (TM) 和两个串联的 C2 结构域（C2A 和 C2B）。本研究旨在使用分子动力学模拟来阐明 Ca2+ 结合的突触结合蛋白-1，通过同时与 VM 和 PM 结合，将它们聚集在一起进行融合。尽管 C2A 通过两个 Ca2+ 结合环与 VM 稳定结合，但 C2B 有部分解离的倾向。重要的是，TM-C2A 接头中的酸性基序与 VM 竞争与 C2B 的相互作用，从而将其方向翻转为面对 PM。随后，C2B 很容易通过多元簇和 Ca2+ 结合环与 PM 相关联。由此产生的由突触结合蛋白 1 触发膜融合的机制模型与许多实验观察一致。