Architecture of the mycobacterial type VII secretion system
Architecture of the mycobacterial type VII secretion system
复制标题
DOI：
10.1038/s41586-019-1633-1
复制
发表时间：
2019-12-12
期刊：
影响因子：
64.8
通讯作者：
Geibel, Sebastian
中科院分区：
文献类型：
--
作者：
Famelis, Nikolaos;Rivera-Calzada, Angel;Geibel, Sebastian
致病性分枝杆菌（如结核分枝杆菌）的宿主感染由VII型分泌系统分泌的毒力因子促进（1）。VII型分泌机制的分子理解由于缺乏完全组装的分泌器的三维结构而受到阻碍。在这里，我们报告的膜包埋的核心复合物的ESX-3/VII型分泌系统从耻垢分枝杆菌的冷冻电镜结构。ESX-3分泌机器的核心由四种蛋白质组分组成-EccB 3，EccC 3，EccD 3和EccE 3，化学计量为1：1：2：1-形成两个相同的原聚体。EccC 3偶联蛋白包含四个ATP酶结构域的柔性阵列，其通过茎结构域连接到膜。与茎相邻的未知功能结构域（DUF）被鉴定为分泌所必需的ATP酶结构域。EccB 3主要是周质的，但一小部分穿过膜并接触茎域。这表明，在茎域的构象变化触发的底物结合在远端的EccC 3和随后的ATP水解的DUF-可以耦合到底物分泌到周质。我们的研究结果表明，VII型分泌系统的结构与其他已知的分泌机器明显不同（2），并提供了对这些系统的结构理解，这将有助于设计针对细菌毒力的抗菌策略。
Host infection by pathogenic mycobacteria, such as Mycobacterium tuberculosis, is facilitated by virulence factors that are secreted by type VII secretion systems(1). A molecular understanding of the type VII secretion mechanism has been hampered owing to a lack of three-dimensional structures of the fully assembled secretion apparatus. Here we report the cryo-electron microscopy structure of a membrane-embedded core complex of the ESX-3/type VII secretion system from Mycobacterium smegmatis. The core of the ESX-3 secretion machine consists of four protein components-EccB3, EccC3, EccD3 and EccE3, in a 1:1:2:1 stoichiometry-which form two identical protomers. The EccC3 coupling protein comprises a flexible array of four ATPase domains, which are linked to the membrane through a stalk domain. The domain of unknown function (DUF) adjacent to the stalk is identified as an ATPase domain that is essential for secretion. EccB3 is predominantly periplasmatic, but a small segment crosses the membrane and contacts the stalk domain. This suggests that conformational changes in the stalk domain-triggered by substrate binding at the distal end of EccC3 and subsequent ATP hydrolysis in the DUF-could be coupled to substrate secretion to the periplasm. Our results reveal that the architecture of type VII secretion systems differs markedly from that of other known secretion machines(2), and provide a structural understanding of these systems that will be useful for the design of antimicrobial strategies that target bacterial virulence.