Munc18-1调控神经递质释放中SNARE复合物组装的分子机制研究

SNARE复合物介导的膜融合受Sec1/Munc18家族蛋白重要调控，Munc18-1作为Sec1/Munc18家族最重要一员，通过多种机制调控神经突触囊泡分泌。近年来Munc18-1通过结构动态变化调控囊泡分泌受到广泛关注，但是具体调控机制仍有待研究。我们和其他研究组揭示了Munc18-1结构域3a通过构象变化调控SNARE复合物组装并促进囊泡成熟的分子机制。同时在研究中发现其临近的β-hairpin也存在明显构象变化，且对SNARE复合物组装有重要调控作用，这提示β-hairpin可能作为分子开关，通过其构象变化调控SNARE复合物组装及其介导的膜融合。我们通过在体内监测β-hairpin对突触囊泡分泌的影响，在体外监测其构象变化及调控机制，进一步揭示Munc18-1构象变化对SNARE复合物介导膜融合的重要性。上述研究有助于更好地理解Munc18-1功能及神经递质分泌过程。

Sec1/Munc18 (SM) proteins play a pivotal role in regulating membrane fusion mediated by SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) complex. The neuronal SM protein Munc18-1, is required for the fusion of synaptic vesicles with the presynaptic plasma membrane through various mechanisms. Recent years, the regulation of Munc18-1 by its structure dynamic changes on the secretion of vesicles has attracted widespread attention. However, the specific physiological significance and regulatory mechanism remain unclear. We and other groups have revealed that Munc18-1 domain 3a acts as a molecular switch that gates SNARE complex assembly and promotes priming of synaptic vesicles via conformational change in loop region. Meanwhile, our data showed that the β-hairpin adjacent to the loop region exhibits a significant conformational change and regulates SNARE assembly. Thus, these results suggest the β-hairpin might act as another molecular switch to regulate SNARE assembly and membrane fusion through changing its conformation. By monitoring the effect of β-hairpin on synaptic vesicle secretion in vivo, the conformational change and regulatory mechanism of β-hairpin in vitro, we will reveal the importance of Munc18-1 in SNARE complex-mediated membrane fusion. This study will deepen our understanding in the pivotal function of Munc18-1 and the processes of neurotransmitters secretion.