Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis
Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis
复制标题
Munc13s 诱导的突触蛋白连接区构象变化启动突触胞吐作用中 SNARE 复合体的形成
DOI：
10.15252/embj.201695775
复制
发表时间：
2017-03-15
期刊：
影响因子：
11.4
通讯作者：
Ma, Cong
中科院分区：
文献类型：
--
作者：
Wang, Shen;Choi, Ucheor B.;Ma, Cong
可溶性N - 乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白 syntaxin - 1在与Munc18 - 1结合时呈现闭合构象，这会阻止其与synaptobrevin - 2和SNAP - 25结合形成三元SNARE复合物。尽管已知Munc13 - 1的MUN结构域催化从Munc18 - 1 / syntaxin - 1复合物到SNARE复合物的转变，但其分子机制尚不清楚。在此，我们确定了syntaxin - 1连接区的两个保守残基（R151，I155）是与MUN结构域相互作用的关键位点。这种相互作用对于体外SNARE复合物的形成以及神经元培养物中突触小泡的预处理至关重要。此外，这种相互作用对于三方Munc18 - 1 / syntaxin - 1 / MUN复合物很重要，在该复合物中，syntaxin - 1仍然呈现与Munc18 - 1紧密结合的闭合构象，而syntaxin - 1连接区改变其构象，类似于syntaxin - 1的LE突变体与Munc18 - 1结合时的构象。我们认为，由Munc13 - 1诱导的syntaxin - 1连接区的构象变化启动了神经系统中三元SNARE复合物的形成。
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1 adopts a closed conformation when bound to Munc18-1, preventing binding to synaptobrevin- 2 and SNAP-25 to form the ternary SNARE complex. Although it is known that the MUN domain of Munc13-1 catalyzes the transition from the Munc18-1/syntaxin-1 complex to the SNARE complex, the molecular mechanism is unclear. Here, we identified two conserved residues (R151, I155) in the syntaxin1 linker region as key sites for the MUN domain interaction. This interaction is essential for SNARE complex formation in vitro and synaptic vesicle priming in neuronal cultures. Moreover, this interaction is important for a tripartite Munc18-1/syntaxin-1/MUN complex, in which syntaxin-1 still adopts a closed conformation tightly bound to Munc18-1, whereas the syntaxin-1 linker region changes its conformation, similar to that of the LE mutant of syntaxin-1 when bound to Munc18-1. We suggest that the conformational change of the syntaxin-1 linker region induced by Munc13-1 initiates ternary SNARE complex formation in the neuronal system.