PDF(Pubmed)
Abstract：
Synaptotagmin-1 (Syt1) is a calcium sensor that regulates synaptic vesicle fusion in synchronous neurotransmitter release. Syt1 interacts with negatively charged lipids and the SNARE complex to control the fusion event. However, it remains incompletely understood how Syt1 mediates Ca2+-trigged synaptic vesicle fusion. Here, we discovered that Syt1 undergoes liquid-liquid phase separation (LLPS) to form condensates both in vitro and in living cells. Syt1 condensates play a role in vesicle attachment to the PM and efficiently recruit SNAREs and complexin, which may facilitate the downstream synaptic vesicle fusion. We observed that Syt1 condensates undergo a liquid-to-gel-like phase transition, reflecting the formation of Syt1 oligomers. The phase transition can be blocked or reversed by Ca2+, confirming the essential role of Ca2+ in Syt1 oligomer disassembly. Finally, we showed that the Syt1 mutations causing Syt1-associated neurodevelopmental disorder impair the Ca2+-driven phase transition. These findings reveal that Syt1 undergoes LLPS and a Ca2+-sensitive phase transition, providing new insights into Syt1-mediated vesicle fusion.
摘要：
Synaptotagmin-1（Syt1）是一种钙传感器，可调节突触小泡融合的同步神经递质释放。Syt1与带负电荷的脂质和SNARE复合物相互作用以控制融合事件。然而,目前尚不清楚Syt1如何介导Ca2+触发的突触小泡融合。这里,我们发现Syt1经历液-液相分离（LLPS）以在体外和活细胞中形成缩合物。Syt1缩合物在囊泡与PM的附着中发挥作用，并有效地招募SNARE和复合物，这可能促进下游突触小泡融合。我们观察到Syt1冷凝物经历了液体到凝胶状的相变，反映Syt1低聚物的形成。相变可以被Ca2+阻断或逆转，证实了Ca2+在Syt1低聚物分解中的重要作用。最后,我们发现Syt1突变导致Syt1相关的神经发育障碍损害了Ca2+驱动的相变。这些发现表明，Syt1经历了LLPS和Ca2+敏感的相变，为Syt1介导的囊泡融合提供新的见解。
