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In Situ Molecular Architecture of the Helicobacter pylori Cag Type IV Secretion System

dc.contributor.authorHu, Bo
dc.contributor.authorKhara, Pratick
dc.contributor.authorSong, Liqiang
dc.contributor.authorLin, Aung Soe
dc.contributor.authorFrick-Cheng, Arwen E.
dc.contributor.authorHarvey, M. Lorena
dc.contributor.authorCover, Timothy L.
dc.contributor.authorChristie, Peter J.
dc.identifier.citationHu B, Khara P, Song L, Lin AS, Frick-Cheng AE, Harvey ML, Cover TL, Christie PJ.2019.In situmolecular architecture of theHelicobacter pyloriCag type IV secretionsystem. mBio 10:e00849-19.
dc.description.abstractHelicobacter pylori colonizes about half of humans worldwide, and its presence in the gastric mucosa is associated with an increased risk of gastric adenocarcinoma, gastric lymphoma, and peptic ulcer disease. H. pylori strains carrying the cag pathogenicity island (cagPAI) are associated with increased risk of disease progression. The cagPAI encodes the Cag type IV secretion system (Cag(T4SS)), which delivers the CagA oncoprotein and other effector molecules into human gastric epithelial cells. We visualized structures of native and mutant Cag(T4SS) machines on the H. pylori cell envelope by cryoelectron tomography. Individual H. pylori cells contain multiple Cag(T4SS) nanomachines, each composed of a wheel-shaped outer membrane complex (OMC) with 14-fold symmetry and an inner membrane complex (IMC) with 6-fold symmetry. CagX, CagY, and CagM are required for assembly of the OMC, whereas strains lacking Cag3 and CagT produce outer membrane complexes lacking peripheral components. The IMC, which has never been visualized in detail, is configured as six tiers in cross-section view and three concentric rings surrounding a central channel in end-on view. The IMC contains three T4SS ATPases: (i) VirB4-like CagE, arranged as a hexamer of dimers at the channel entrance; (ii) a hexamer of VirB11-like Cag alpha, docked at the base of the CagE hexamer; and (iii) VirD4-like Cag beta and other unspecified Cag subunits, associated with the stacked CagE/Cag alpha complex and forming the outermost rings. The Cag(T4SS) and recently solved Legionella pneumophila Dot/Icm system comprise new structural prototypes for the T4SS superfamily. IMPORTANCE Bacterial type IV secretion systems (T4SSs) have been phylogenetically grouped into two subfamilies. The T4ASSs, represented by the Agrobacterium tumefaciens VirB/VirD4(T4SS), include "minimized" machines assembled from 12 VirB-and VirD4-like subunits and compositionally larger systems such as the Helicobacter pylori Cag(T4SS). T4BSSs encompass systems closely related in subunit composition to the Legionella pneumophila Dot/Icm(T4SS). Here, we present structures of native and mutant H. pylori Cag machines determined by in situ cryoelectron tomography. We identify distinct outer and inner membrane complexes and, for the first time, visualize structural contributions of all three "signature" ATPases of T4SSs at the cytoplasmic entrance of the translocation channel. Despite their evolutionary divergence, the Cag(T4SS) aligns structurally much more closely to the Dot/Icm(T4SS) than an available VirB/VirD4 subcomplex. Our findings highlight the diversity of T4SSs and suggest a structural classification scheme in which T4SSs are grouped as minimized VirB/VirD4-like or larger Cag-like and Dot/Icm-like systems.en_US
dc.description.sponsorshipB.H. was supported in part by McGovern Medical School start-up funds and the Welch Foundation (AU-1953-20180324). P.J.C. was supported by NIH R01GM48476. B.H. and P.J.C. were supported in part by NIH R21AI142378 and by NIH DK056338, which supports the Texas Medical Center Digestive Diseases Center. T.L.C. was supported by NIH AI118932, CA116087, and Department of Veterans Affairs grant 1I01BX004447.en_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.
dc.subjectHelicobacter pylorien_US
dc.subjectcryoelectron tomographyen_US
dc.subjectprotein translocationen_US
dc.subjecttype IV secretionen_US
dc.subjecttrag-like proteinsen_US
dc.subjectagrobacterium virb10en_US
dc.subjectcore complesen_US
dc.subjectDNA transferen_US
dc.subject.lcshProtein targeting and translocationen_US
dc.titleIn Situ Molecular Architecture of the Helicobacter pylori Cag Type IV Secretion Systemen_US

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