A hemifused complex is the hub in a network of pathways to membrane fusion.
A hemifused complex is the hub in a network of pathways to membrane fusion.
复制标题
半融合复合体是膜融合途径网络中的枢纽。
DOI：
10.1016/j.bpj.2022.12.003
复制
发表时间：
2023
影响因子：
3.4
通讯作者：
O'Shaughnessy,Ben
中科院分区：
文献类型：
--
作者：
Warner,JasonM;An,Dong;Stratton,BenjaminS;O'Shaughnessy,Ben
膜融合是从神经传递到受精等许多基本过程的关键步骤。40多年来，由钙或其他阳离子物种驱动的无蛋白融合提供了生物融合的简化模型，但其机制仍然知之甚少。阳离子介导的膜融合和渗透对于基于细胞穿透肽或携带阳离子的脂质纳米颗粒的药物递送策略本身是必不可少的。实验研究表明，钙驱动阴离子膜的半融合的中间体，构成了网络的途径的枢纽，但途径选择机制是未知的。在这里，我们开发了一个数学模型，确定网络枢纽作为一个高度动态的半融合复杂。多价阳离子在短暂的瞬间驱动相互作用的囊泡之间的这种高张力半融合界面的扩张。该界面的命运决定了融合、死端半融合或囊泡溶解的结果。该模型再现了无法解释的发现，即钙驱动的融合囊泡与平面膜通常在半融合时停滞，我们表明平衡的半融合状态是一种新型的透镜状复合物。因此，膜融合动力学遵循途径网络内的随机轨迹，结果权重由半融合复合物中间体设定。
Membrane fusion is a critical step for many essential processes, from neurotransmission to fertilization. For over 40 years, protein-free fusion driven by calcium or other cationic species has provided a simplified model of biological fusion, but the mechanisms remain poorly understood. Cation-mediated membrane fusion and permeation are essential in their own right to drug delivery strategies based on cell-penetrating peptides or cation-bearing lipid nanoparticles. Experimental studies suggest calcium drives anionic membranes to a hemifused intermediate that constitutes a hub in a network of pathways, but the pathway selection mechanism is unknown. Here we develop a mathematical model that identifies the network hub as a highly dynamic hemifusion complex. Multivalent cations drive expansion of this high-tension hemifusion interface between interacting vesicles during a brief transient. The fate of this interface determines the outcome, either fusion, dead-end hemifusion, or vesicle lysis. The model reproduces the unexplained finding that calcium-driven fusion of vesicles with planar membranes typically stalls at hemifusion, and we show the equilibrated hemifused state is a novel lens-shaped complex. Thus, membrane fusion kinetics follow a stochastic trajectory within a network of pathways, with outcome weightings set by a hemifused complex intermediate.