Mechanism of regulation of the Helicobacter pylori Cagβ ATPase by CagZ

• Published in: Nature communications Vol. 14; no. 1; pp. 479 - 13
• Main Authors: Wu, Xiuling, Zhao, Yanhe, Zhang, Hong, Yang, Wendi, Yang, Jinbo, Sun, Lifang, Jiang, Meiqin, Wang, Qin, Wang, Qianchao, Ye, Xianren, Zhang, Xuewu, Wu, Yunkun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/47; 38; 42/70; 45/22; 45/23; 45/29; 45/47; 45/77; 49/23; 631/326/421; 631/535/1266; 692/420/254; Adenosine triphosphatase; Adenosine Triphosphatases - metabolism; Antigens, Bacterial - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biology; Crystal structure; Effector cells; Epithelial cells; Epithelium; Gene expression; Helicobacter pylori; Helicobacter pylori - metabolism; Humanities and Social Sciences; Kinases; Laboratories; multidisciplinary; Pathogenesis; Proteins; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Secretion; Trinucleotide repeats; Type IV Secretion Systems - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36218-4

The transport of the CagA effector into gastric epithelial cells by the Cag Type IV secretion system (Cag T4SS) of Helicobacter pylori ( H. pylori ) is critical for pathogenesis. CagA is recruited to Cag T4SS by the Cagβ ATPase. CagZ, a unique protein in H. pylori , regulates Cagβ-mediated CagA transport, but the underlying mechanisms remain unclear. Here we report the crystal structure of the cytosolic region of Cagβ, showing a typical ring-like hexameric assembly. The central channel of the ring is narrow, suggesting that CagA must unfold for transport through the channel. Our structure of CagZ in complex with the all-alpha domain (AAD) of Cagβ shows that CagZ adopts an overall U-shape and tightly embraces Cagβ. This binding mode of CagZ is incompatible with the formation of the Cagβ hexamer essential for the ATPase activity. CagZ therefore inhibits Cagβ by trapping it in the monomeric state. Based on these findings, we propose a refined model for the transport of CagA by Cagβ. Cagβ is an ATPase in the H. pylori CagType4 secretion system essential for delivering the CagA effector to host cells. Here, authors present crystal structures of hexameric apo-Cagβ and Cagβ trapped in the monomeric state by its regulator CagZ, uncovering the regulatory mechanisms of Cagβ.