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Cryo-EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution.

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Zhang K, Zhang H, Li S, Pintilie GD, Mou TC, Gao Y, Zhang Q, van den Bedem H, Schmid MF, Au SWN, Chiu W
OpenAccess logo Proc Natl Acad Sci U S A 116 6800-6805 (2019)
Related entries: 6nyf, 6nyg, 6nyl, 6nym, 6nyn

Cited: 21 times
EuropePMC logo PMID: 30894496

Abstract

Human 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 β-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.

Articles - 6nyj mentioned but not cited (1)

  1. Cryo-EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution. Zhang K, Zhang H, Li S, Pintilie GD, Mou TC, Gao Y, Zhang Q, van den Bedem H, Schmid MF, Au SWN, Chiu W. Proc Natl Acad Sci U S A 116 6800-6805 (2019)


Reviews citing this publication (3)

  1. Cryo-electron tomography related radiation-damage parameters for individual-molecule 3D structure determination. Xue H, Zhang M, Liu J, Wang J, Ren G. Front Chem 10 889203 (2022)
  2. Helicobacter pylori and Epstein-Barr virus infection in cell polarity alterations. Baral B, Kandpal M, Ray A, Jana A, Yadav DS, Sachin K, Mishra A, Baig MS, Jha HC. Folia Microbiol (Praha) (2023)
  3. Phylogenetic Classification and Functional Review of Autotransporters. Clarke KR, Hor L, Pilapitiya A, Luirink J, Paxman JJ, Heras B. Front Immunol 13 921272 (2022)

Articles citing this publication (17)

  1. Evolving data standards for cryo-EM structures. Lawson CL, Berman HM, Chiu W. Struct Dyn 7 014701 (2020)
  2. Deep Learning to Predict Protein Backbone Structure from High-Resolution Cryo-EM Density Maps. Si D, Moritz SA, Pfab J, Hou J, Cao R, Wang L, Wu T, Cheng J. Sci Rep 10 4282 (2020)
  3. Inhibition mechanisms of AcrF9, AcrF8, and AcrF6 against type I-F CRISPR-Cas complex revealed by cryo-EM. Zhang K, Wang S, Li S, Zhu Y, Pintilie GD, Mou TC, Schmid MF, Huang Z, Chiu W. Proc Natl Acad Sci U S A 117 7176-7182 (2020)
  4. An Immune Signature for Risk Stratification and Therapeutic Prediction in Helicobacter pylori-Infected Gastric Cancer. Geng H, Dong Z, Zhang L, Yang C, Li T, Lin Y, Ke S, Xia X, Zhang Z, Zhao G, Zhu C. Cancers (Basel) 14 3276 (2022)
  5. Construction and preservation of a stable and highly expressed recombinant Helicobacter pylori vacuolating cytotoxin A with apoptotic activity. Yuan LZ, Shi X, Tang D, Zheng SP, Xiao ZM, Wang F. BMC Microbiol 21 229 (2021)
  6. Topological crossing in the misfolded Tetrahymena ribozyme resolved by cryo-EM. Li S, Palo MZ, Pintilie G, Zhang X, Su Z, Kappel K, Chiu W, Zhang K, Das R. Proc Natl Acad Sci U S A 119 e2209146119 (2022)
  7. A quantitative single-cell assay for retrograde membrane traffic enables rapid detection of defects in cellular organization. Luong P, Li Q, Chen PF, Wrighton PJ, Chang D, Dwyer S, Bayer MT, Snapper SB, Hansen SH, Thiagarajah JR, Goessling W, Lencer WI. Mol Biol Cell 31 511-519 (2020)
  8. CryoEM analysis of small plant biocatalysts at sub-2 Å resolution. Dimos N, Helmer CPO, Chánique AM, Wahl MC, Kourist R, Hilal T, Loll B. Acta Crystallogr D Struct Biol 78 113-123 (2022)
  9. DeepTracer for fast de novo cryo-EM protein structure modeling and special studies on CoV-related complexes. Pfab J, Phan NM, Si D. Proc Natl Acad Sci U S A 118 (2021)
  10. Filling Adeno-Associated Virus Capsids: Estimating Success by Cryo-Electron Microscopy. Subramanian S, Maurer AC, Bator CM, Makhov AM, Conway JF, Turner KB, Marden JH, Vandenberghe LH, Hafenstein SL. Hum. Gene Ther. 30 1449-1460 (2019)
  11. Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants. Caston RR, Sierra JC, Foegeding NJ, Truelock MD, Campbell AM, Frick-Cheng AE, Bimczok D, Wilson KT, McClain MS, Cover TL. Infect Immun 88 (2020)
  12. Functional Properties of Oligomeric and Monomeric Forms of Helicobacter pylori VacA Toxin. Caso GC, McClain MS, Erwin AL, Truelock MD, Campbell AM, Leasure CS, Nagel M, Schey KL, Lacy DB, Ohi MD, Cover TL. Infect Immun 89 e0034821 (2021)
  13. Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells. Seeger AY, Zaidi F, Alhayek S, Jones RM, Zohair H, Holland RL, Kim I-J, Blanke SR. mBio 14 e0211723 (2023)
  14. New genotypes of Helicobacter Pylori VacA d-region identified from global strains. Soyfoo DM, Doomah YH, Xu D, Zhang C, Sang HM, Liu YY, Zhang GX, Jiang JX, Xu SF. BMC Mol Cell Biol 22 4 (2021)
  15. Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis. Tak U, Dokland T, Niederweis M. Nat Commun 12 394 (2021)
  16. Snapshots of the first-step self-splicing of Tetrahymena ribozyme revealed by cryo-EM. Zhang X, Li S, Pintilie G, Palo MZ, Zhang K. Nucleic Acids Res 51 1317-1325 (2023)
  17. Snapshots of the second-step self-splicing of Tetrahymena ribozyme revealed by cryo-EM. Li S, Palo MZ, Zhang X, Pintilie G, Zhang K. Nat Commun 14 1294 (2023)


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