Center for Microbiome Research of Med-X Institute, Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Cell Rep. 2023 Jul 25;42(7):112781. doi: 10.1016/j.celrep.2023.112781. Epub 2023 Jul 7.
Type VI secretion system is widely used in Gram-negative bacteria for injecting toxic effectors into neighboring prokaryotic or eukaryotic cells. Various effectors can be loaded onto the T6SS delivery tube via its core components: Hcp, VgrG, or PAAR. Here, we report 2.8-Å resolution cryo-EM structure of intact T6SS Hcp5-VgrG-PAAR cargo delivery system and crystal structure of unbound Hcp5 from B. fragilis NCTC 9343. Loading of Hcp5 hexameric ring onto VgrG causes expansion of its inner cavity and external surface, explaining how structural changes could be propagated to regulate co-polymerization and surrounding contractile sheath. High-affinity binding between Hcp and VgrG causes entropically unfavorable structuring of long loops. Furthermore, interactions between VgrG trimer and Hcp hexamer are asymmetric, with three of the six Hcp monomers exhibiting a major loop flip. Our study provides insights into the assembly, loading, and firing of T6SS nanomachine that contributes to bacterial inter-species competition and host interactions.
VI 型分泌系统广泛存在于革兰氏阴性菌中，用于将毒性效应器注入邻近的原核或真核细胞。各种效应器可以通过其核心组件：Hcp、VgrG 或 PAAR 加载到 T6SS 输送管上。在这里，我们报道了完整的 T6SS Hcp5-VgrG-PAAR 货物输送系统的 2.8-埃分辨率冷冻电镜结构和无结合 Hcp5 的晶体结构从脆弱拟杆菌 NCTC 9343。Hcp5 六聚体环加载到 VgrG 上会导致其内腔和外表面扩张，解释了结构变化如何传播以调节共聚合和周围的收缩鞘。Hcp 和 VgrG 之间的高亲和力结合导致长环的熵不利结构。此外，VgrG 三聚体和 Hcp 六聚体之间的相互作用是不对称的，六个 Hcp 单体中的三个表现出主要环翻转。我们的研究为 T6SS 纳米机器的组装、加载和发射提供了深入的了解，这有助于细菌种间竞争和宿主相互作用。
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