Cryo-EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution
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AbstractHuman gastric pathogen Helicobacter pylori (H. pylori) is the primary risk factor for gastric cancer and is one of the most prevalent carcinogenic infectious agents. Vacuolating cytotoxin A (VacA) is a key virulence factor secreted by H. pylori and induces multiple cellular responses. Although structural and functional studies of VacA have been extensively performed, the high-resolution structure of a full-length VacA protomer and the molecular basis of its oligomerization are still unknown. Here, we use cryoelectron microscopy to resolve 10 structures of VacA assemblies, including monolayer (hexamer and heptamer) and bilayer (dodecamer, tridecamer, and tetradecamer) oligomers. The models of the 88-kDa full-length VacA protomer derived from the near-atomic resolution maps are highly conserved among different oligomers and show a continuous right-handed p-helix made up of two domains with extensive domain-domain interactions. The specific interactions between adjacent protomers in the same layer stabilizing the oligomers are well resolved. For double-layer oligomers, we found short- and/or long-range hydrophobic interactions between protomers across the two layers. Our structures and other previous observations lead to a mechanistic model wherein VacA hexamer would correspond to the prepore-forming state, and the N-terminal region of VacA responsible for the membrane insertion would undergo a large conformational change to bring the hydrophobic transmembrane region to the center of the oligomer for the membrane channel formation.
All Author(s) ListKaiming Zhang, Huawei Zhang, Shanshan Li, Grigore D. Pintilie,Tung-Chung Mou, Yuanzhu Gao, Qinfen Zhang, Henry van den Bedem, Michael F. Schmid, Shannon Wing Ngor Au, Wah Chiu
Journal nameProceedings of the National Academy of Sciences
Year2019
Month4
Day2
Volume Number116
Issue Number14
PublisherNational Academy of Sciences
Pages6800 - 6805
ISSN0027-8424
LanguagesEnglish-United States

Last updated on 2020-20-09 at 00:52