An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA

Conradi J, Tegtmeyer N, Wozna M, Wißbrock M, Michalek C, Gagell C, Cover TL, Frank R, Sewald N, Backert S (2012)
Frontiers in Cellular and Infection Microbiology 2: 70.

Download
OA
Journal Article | Original Article | Published | English
Author
; ; ; ; ; ; ; ; ;
Abstract
Helicobacter pylori is a specific gastric pathogen that colonizes the stomach in more than 50% of the world’s human population. Infection with this bacterium can induce several types of gastric pathology, ranging from chronic gastritis to peptic ulcers and even adenocarcinoma. Virulent H. pylori isolates encode components of a type IV secretion system (T4SS), which form a pilus for the injection of virulence proteins such as CagA into host target cells. This is accomplished by a specialized adhesin on the pilus surface, the protein CagL, a putative VirB5 ortholog, which binds to host cell β1 integrin, triggering subsequent delivery of CagA across the host cell membrane. Like the human extracellular matrix protein fibronectin, CagL contains an RGD (Arg-Gly-Asp) motif and is able to trigger intracellular signaling pathways by RGD-dependent binding to integrins. While CagL binding to host cells is mediated primarily by the RGD motif, we identified an auxiliary binding motif for CagL–integrin interaction. Here, we report on a surface exposed FEANE (Phe-Glu-Ala-Asn-Glu) interaction motif in spatial proximity to the RGD sequence, which enhances the interactions of CagL with integrins. It will be referred to as RGD helper sequence (RHS). Competitive cell adhesion assays with recombinant wild type CagL and point mutants, competition experiments with synthetic cyclic and linear peptides, and peptide array experiments revealed amino acids essential for the interaction of the RHS motif with integrins. Infection experiments indicate that the RHS motif plays a role in the early interaction of H. pylori T4SS with integrin, to trigger signaling and to inject CagA into host cells. We thus postulate that CagL is a versatile T4SS surface protein equipped with at least two motifs to promote binding to integrins, thereby causing aberrant signaling within host cells and facilitating translocation of CagA into host cells, thus contributing directly to H. pylori pathogenesis.
Publishing Year
ISSN
eISSN
Financial disclosure
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft and the Open Access Publication Fund of Bielefeld University.
PUB-ID

Cite this

Conradi J, Tegtmeyer N, Wozna M, et al. An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology. 2012;2:70.
Conradi, J., Tegtmeyer, N., Wozna, M., Wißbrock, M., Michalek, C., Gagell, C., Cover, T. L., et al. (2012). An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology, 2, 70. doi:10.3389/fcimb.2012.00070
Conradi, J., Tegtmeyer, N., Wozna, M., Wißbrock, M., Michalek, C., Gagell, C., Cover, T. L., Frank, R., Sewald, N., and Backert, S. (2012). An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology 2, 70.
Conradi, J., et al., 2012. An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology, 2, p 70.
J. Conradi, et al., “An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA”, Frontiers in Cellular and Infection Microbiology, vol. 2, 2012, pp. 70.
Conradi, J., Tegtmeyer, N., Wozna, M., Wißbrock, M., Michalek, C., Gagell, C., Cover, T.L., Frank, R., Sewald, N., Backert, S.: An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology. 2, 70 (2012).
Conradi, Jens, Tegtmeyer, Nicole, Wozna, Marta, Wißbrock, Marco, Michalek, Carmela, Gagell, Corinna, Cover, Timothy L., Frank, Ronald, Sewald, Norbert, and Backert, Steffen. “An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA”. Frontiers in Cellular and Infection Microbiology 2 (2012): 70.
All files available under the following license(s):
Copyright Statement:
This Item is protected by copyright and/or related rights. [...]
Main File(s)
Access Level
OA Open Access
Last Uploaded
2017-11-09T10:05:01Z

This data publication is cited in the following publications:
This publication cites the following data publications:

30 Citations in Europe PMC

Data provided by Europe PubMed Central.

A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system.
Gorrell RJ, Guan J, Xin Y, Tafreshi MA, Hutton ML, McGuckin MA, Ferrero RL, Kwok T., Cell Microbiol 15(4), 2013
PMID: 23107019
Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori.
Salama NR, Hartung ML, Müller A., Nat Rev Microbiol 11(6), 2013
PMID: 23652324
A helical RGD motif promoting cell adhesion: crystal structures of the Helicobacter pylori type IV secretion system pilus protein CagL.
Barden S, Lange S, Tegtmeyer N, Conradi J, Sewald N, Backert S, Niemann HH., Structure 21(11), 2013
PMID: 24076404
Research advances in the study of Campylobacter, Helicobacter, and related organisms.
Merrell DS, Stintzi A., Front Cell Infect Microbiol 2(), 2012
PMID: 23267439

19 References

Data provided by Europe PubMed Central.

Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins αVβ3 and α5β1.
Conradi J, Huber S, Gaus K, Mertink F, Royo Gracia S, Strijowski U, Backert S, Sewald N., Amino Acids 43(1), 2012
PMID: 21915696
Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner.
Jimenez-Soto LF, Kutter S, Sewald X, Ertl C, Weiss E, Kapp U, Rohde M, Pirch T, Jung K, Retta SF, Terradot L, Fischer W, Haas R., PLoS Pathog. 5(12), 2009
PMID: 19997503
Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism.
Kwok T, Backert S, Schwarz H, Berger J, Meyer TF., Infect. Immun. 70(4), 2002
PMID: 11895977
Helicobacter pylori induces AGS cell motility and elongation via independent signaling pathways.
Moese S, Selbach M, Kwok T, Brinkmann V, Konig W, Meyer TF, Backert S., Infect. Immun. 72(6), 2004
PMID: 15155677
Coadaptation of Helicobacter pylori and humans: ancient history, modern implications.
Atherton JC, Blaser MJ., J. Clin. Invest. 119(9), 2009
PMID: 19729845
c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains.
Mueller D, Tegtmeyer N, Brandt S, Yamaoka Y, De Poire E, Sgouras D, Wessler S, Torres J, Smolka A, Backert S., J. Clin. Invest. 122(4), 2012
PMID: 22378042
Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse.
Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, Yamada G, Azuma T, Hatakeyama M., Proc. Natl. Acad. Sci. U.S.A. 105(3), 2008
PMID: 18192401
Helicobacter pylori: gastric cancer and beyond.
Polk DB, Peek RM Jr., Nat. Rev. Cancer 10(6), 2010
PMID: 20495574
Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit.
Saha A, Backert S, Hammond CE, Gooz M, Smolka AJ., Gastroenterology 139(1), 2010
PMID: 20303353
Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface.
Shaffer CL, Gaddy JA, Loh JT, Johnson EM, Hill S, Hennig EE, McClain MS, McDonald WH, Cover TL., PLoS Pathog. 7(9), 2011
PMID: 21909278
Structure of integrin alpha5beta1 in complex with fibronectin.
Takagi J, Strokovich K, Springer TA, Walz T., EMBO J. 22(18), 2003
PMID: 12970173
The RGD motif in fibronectin is essential for development but dispensable for fibril assembly.
Takahashi S, Leiss M, Moser M, Ohashi T, Kitao T, Heckmann D, Pfeifer A, Kessler H, Takagi J, Erickson HP, Fassler R., J. Cell Biol. 178(1), 2007
PMID: 17591922
A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation.
Tegtmeyer N, Hartig R, Delahay RM, Rohde M, Brandt S, Conradi J, Takahashi S, Smolka AJ, Sewald N, Backert S., J. Biol. Chem. 285(30), 2010
PMID: 20507990
Helicobacter pylori CagL dependent induction of gastrin expression via a novel αvβ5-integrin-integrin linked kinase signalling complex.
Wiedemann T, Hofbaur S, Tegtmeyer N, Huber S, Sewald N, Wessler S, Backert S, Rieder G., Gut 61(7), 2012
PMID: 22287591
Structural and functional characterization of the VirB5 protein from the type IV secretion system encoded by the conjugative plasmid pKM101.
Yeo HJ, Yuan Q, Beck MR, Baron C, Waksman G., Proc. Natl. Acad. Sci. U.S.A. 100(26), 2003
PMID: 14673074

Export

0 Marked Publications

Open Data PUB

Web of Science

View record in Web of Science®

Sources

PMID: 22919661
PubMed | Europe PMC

Search this title in

Google Scholar