Munc13 激活 Munc18-1/syntaxin-1 复合物，并使 Munc18-1 能够引发 SNARE 组装。
Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.
机构信息
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Cognitive Science, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.
出版信息
EMBO J. 2020 Aug 17;39(16):e103631. doi: 10.15252/embj.2019103631. Epub 2020 Jul 9.
Priming of synaptic vesicles involves Munc13-catalyzed transition of the Munc18-1/syntaxin-1 complex to the SNARE complex in the presence of SNAP-25 and synaptobrevin-2; Munc13 drives opening of syntaxin-1 via the MUN domain while Munc18-1 primes SNARE assembly via domain 3a. However, the underlying mechanism remains unclear. In this study, we have identified a number of residues in domain 3a of Munc18-1 that are crucial for Munc13 and Munc18-1 actions in SNARE complex assembly and synaptic vesicle priming. Our results showed that two residues (Q301/K308) at the side of domain 3a mediate the interaction between the Munc18-1/syntaxin-1 complex and the MUN domain. This interaction enables the MUN domain to drive the opening of syntaxin-1 linker region, thereby leading to the extension of domain 3a and promoting synaptobrevin-2 binding. In addition, we identified two residues (K332/K333) at the bottom of domain 3a that mediate the interaction between Munc18-1 and the SNARE motif of syntaxin-1. This interaction ensures Munc18-1 to persistently associate with syntaxin-1 during the conformational change of syntaxin-1 from closed to open, which reinforces the role of Munc18-1 in templating SNARE assembly. Taken together, our data suggest a mechanism by which Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.
囊泡的引发涉及到 Munc13 催化 Munc18-1/syntaxin-1 复合物在 SNAP-25 和 synaptobrevin-2 的存在下向 SNARE 复合物的转变；Munc13 通过 MUN 结构域驱动 syntaxin-1 的开放，而 Munc18-1 通过结构域 3a 引发 SNARE 组装。然而，其潜在的机制仍不清楚。在这项研究中，我们已经确定了 Munc18-1 结构域 3a 中的一些残基，这些残基对于 Munc13 和 Munc18-1 在 SNARE 复合物组装和囊泡引发中的作用至关重要。我们的结果表明，结构域 3a 侧面的两个残基（Q301/K308）介导了 Munc18-1/syntaxin-1 复合物与 MUN 结构域之间的相互作用。这种相互作用使 MUN 结构域能够驱动 syntaxin-1 连接区的开放，从而导致结构域 3a 的延伸，并促进 synaptobrevin-2 的结合。此外，我们在结构域 3a 的底部鉴定了两个残基（K332/K333），它们介导了 Munc18-1 与 syntaxin-1 的 SNARE 基序之间的相互作用。这种相互作用确保了 Munc18-1 在 syntaxin-1 从封闭到开放的构象变化过程中与 syntaxin-1 持续结合，从而增强了 Munc18-1 在模板 SNARE 组装中的作用。总之，我们的数据表明了一种机制，通过该机制，Munc13 激活 Munc18-1/syntaxin-1 复合物，并使 Munc18-1 能够引发 SNARE 组装。
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