VAMP2 regulates phase separation of alpha-synuclein-猫眼课题宝

DOI：

10.1101/2023.06.16.545277

发表时间：

2023-06

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Aishwarya Agarwal;F. Raza;C. Hilcenko;K. Stott;N. Morone;A. Warren;Janin Lautenschläger

α-突触核蛋白（aSYN）是一种与帕金森病（PD）和其他突触核蛋白病有关的小突触蛋白。aSYN已显示经历蛋白质相分离。我们发现，aSYN相分离，在体外和细胞中，是由囊泡相关膜蛋白2（VAMP 2），囊泡陷阱蛋白。我们表明，aSYN相分离是由C-末端静电相互作用，这在细胞中是通过与VAMP 2的相互作用介导的。冷凝物的形成对R-SNARE VAMP 2是特异性的，并且严重依赖于aSYN与脂质膜结合的能力。在体外，VAMP 2的加入降低了aSYN相分离的饱和浓度，这是由其质膜结构域介导的。我们的研究结果描绘了一个分子机制的aSYN相分离的调节，表明一个潜在的开关从分散的相分离状态在囊泡循环。亮点α-突触核蛋白相分离受静电相互作用调节VAMP 2启动细胞内α-突触核蛋白凝聚VAMP 2的质膜结构域内的正电荷启动α-突触核蛋白体外相分离α-突触核蛋白凝聚物在脂质膜上成核并在细胞内组装囊泡结构

Summary Alpha-synuclein (aSYN) is a small synaptic protein that is linked to Parkinson’s disease (PD) and other synucleinopathies. aSYN has been shown to undergo protein phase separation. We found that aSYN phase separation, in vitro and in cells, is regulated by vesicle-associated membrane protein 2 (VAMP2), the vesicular SNARE protein. We show that aSYN phase separation is promoted by C-terminal electrostatic interaction, which in cells is mediated via interaction with VAMP2. The condensate formation is specific for the R-SNARE VAMP2 and critically dependent on aSYN’s capacity to bind to lipid membranes. In vitro, the addition of VAMP2 decreases the saturation concentration of aSYN phase separation, which is mediated by its juxtamembrane domain. Our results delineate a molecular mechanism for the regulation of aSYN phase separation, indicating a potential switch from the dispersed to the phase-separated state during vesicle cycling. Highlights Alpha-synuclein phase separation is regulated by electrostatic interactions VAMP2 initiates alpha-synuclein condensation in cells Positive charges within the juxtamembrane domain of VAMP2 initiate alpha-synuclein phase separation in vitro Alpha-synuclein condensates nucleate on lipid membranes and assemble vesicular structures in cells

VAMP2 regulates phase separation of alpha-synuclein

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