美国斯坦福大学Axel T. Brunger等研究人员合作揭示突触V-ATP酶–突触生长蛋白复合物的结构和拓扑图。相关论文于2024年6月5日在线发表在《自然》杂志上。

研究人员通过对从小鼠大脑中分离出来的功能性突触小泡进行原位冷冻电子断层扫描和单颗粒冷冻电镜观察，发现了突触小泡V-ATP酶和突触生长蛋白之间的明确界面。突触小泡V-ATP酶是一种依赖ATP的质子泵，它能建立跨突触小泡的蛋白质梯度，进而驱动神经递质的吸收。突触生长蛋白及其同系物synaptoporin和synaptogyrin属于突触小泡蛋白家族，其功能尚不清楚。研究人员对突触生长蛋白基因敲除小鼠进行了结构和功能研究，证实了突触生长蛋白是V-ATP酶的相互作用伙伴。

虽然在与突触生长蛋白相互作用时，V-ATP酶的构象几乎不会发生变化，但突触小泡中突触生长蛋白的存在会严重影响V-ATP酶的拷贝数。这种对突触小泡形貌的影响表明，突触生长蛋白有助于突触小泡的生物生成。为了支持这一模型，研究人员观察到突触生长蛋白基因敲除小鼠表现出严重的癫痫易感性，这表明神经递质释放失衡是突触生长蛋白缺失的生理后果。

据悉，突触小泡是一种具有精确定义的蛋白质和脂质组成的细胞器，然而突触小泡生物生成的分子机制却不为人知。

附：英文原文

Title: Structure and topography of the synaptic V-ATPase–synaptophysin complex

Author: Wang, Chuchu, Jiang, Wenhong, Leitz, Jeremy, Yang, Kailu, Esquivies, Luis, Wang, Xing, Shen, Xiaotao, Held, Richard, Adams, Daniel J., Basta, Tamara, Hampton, Lucas, Jian, Ruiqi, Jiang, Lihua, Stowell, Michael H. B., Baumeister, Wolfgang, Guo, Qiang, Brunger, Axel T.

Issue&Volume: 2024-06-05

Abstract: Synaptic vesicles are organelles with a precisely defined protein and lipid composition1,2, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here, we discovered a well-defined interface between the synaptic vesicle V-ATPase and synaptophysin by in situ cryo-electron tomography and single particle cryo-electron microscopy of functional synaptic vesicles isolated from mouse brains3. The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the protein gradient across the synaptic vesicle, which in turn drives the uptake of neurotransmitters4,5. Synaptophysin6 and its paralogs synaptoporin7 and synaptogyrin8 belong to a family of abundant synaptic vesicle proteins whose function is still unclear. We performed structural and functional studies of synaptophysin knockout mice, confirming the identity of synaptophysin as an interaction partner with the V-ATPase. Although there is little change in the conformation of the V-ATPase upon interaction with synaptophysin, the presence of synaptophysin in synaptic vesicles profoundly affects the copy number of V-ATPases. This effect on the topography of synaptic vesicles suggests that synaptophysin assists in their biogenesis. In support of this model, we observed that synaptophysin knockout mice exhibit severe seizure susceptibility, suggesting an imbalance of neurotransmitter release as a physiological consequence of the absence of synaptophysin.

DOI: 10.1038/s41586-024-07610-x

Source: https://www.nature.com/articles/s41586-024-07610-x