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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 1931-41 (2013)
Cited: 45 times
EuropePMC logo PMID: 24076404

Abstract

RGD tripeptide motifs frequently mediate ligand binding to integrins. The type IV secretion system (T4SS) protein CagL of the gastric pathogen Helicobacter pylori also contains an RGD motif. CagL decorates the T4SS pilus and may function as an adhesin for host cells. Whether CagL binds integrins via its RGD motif is under debate. Here, we present crystal structures of CagL revealing an elongated four-helix bundle that appears evolutionarily unrelated to the proposed VirB5 orthologs. The RGD motif is surface-exposed but located within a long α helix. This is unprecedented as previously characterized integrin-binding RGD motifs are located within extended or flexible loops. Yet, adhesion of gastric epithelial cells to CagL was strictly RGD-dependent. Comparison of seven crystallographically independent molecules reveals substantial structural flexibility. Intramolecular disulfide bonds engineered to reduce CagL flexibility resulted in more stable protein, but unable to support cell adhesion. CagL may thus partly unfold during receptor binding.

Reviews - 3zci mentioned but not cited (1)

  1. The Helicobacter pylori Cag Type IV Secretion System. Cover TL, Lacy DB, Ohi MD. Trends Microbiol 28 682-695 (2020)

Articles - 3zci mentioned but not cited (3)

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Reviews citing this publication (15)

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Articles citing this publication (26)

  1. Roles of the putative integrin-binding motif of the human metapneumovirus fusion (f) protein in cell-cell fusion, viral infectivity, and pathogenesis. Wei Y, Zhang Y, Cai H, Mirza AM, Iorio RM, Peeples ME, Niewiesk S, Li J. J. Virol. 88 4338-4352 (2014)
  2. Helicobacter pylori CagL Y58/E59 mutation turns-off type IV secretion-dependent delivery of CagA into host cells. Tegtmeyer N, Lind J, Schmid B, Backert S. PLoS ONE 9 e97782 (2014)
  3. Helicobacter pylori CagL Hypervariable Motif: A Global Analysis of Geographical Diversity and Association With Gastric Cancer. Gorrell RJ, Zwickel N, Reynolds J, Bulach D, Kwok T. J. Infect. Dis. 213 1927-1931 (2016)
  4. Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains. Bönig T, Olbermann P, Bats SH, Fischer W, Josenhans C. Sci Rep 6 38101 (2016)
  5. Overexpression of serine protease HtrA enhances disruption of adherens junctions, paracellular transmigration and type IV secretion of CagA by Helicobacter pylori. Harrer A, Boehm M, Backert S, Tegtmeyer N. Gut Pathog 9 40 (2017)
  6. Structure of a three-dimensional domain-swapped dimer of the Helicobacter pylori type IV secretion system pilus protein CagL. Barden S, Schomburg B, Conradi J, Backert S, Sewald N, Niemann HH. Acta Crystallogr. D Biol. Crystallogr. 70 1391-1400 (2014)
  7. Preservation of Helicobacter pylori CagA Translocation and Host Cell Proinflammatory Responses in the Face of CagL Hypervariability at Amino Acid Residues 58/59. Tafreshi M, Zwickel N, Gorrell RJ, Kwok T. PLoS ONE 10 e0133531 (2015)
  8. Helicobacter pylori HP0231 Influences Bacterial Virulence and Is Essential for Gastric Colonization. Zhong Y, Anderl F, Kruse T, Schindele F, Jagusztyn-Krynicka EK, Fischer W, Gerhard M, Mejías-Luque R. PLoS ONE 11 e0154643 (2016)
  9. Molecular dissection of protein-protein interactions between integrin α5β1 and the Helicobacter pylori Cag type IV secretion system. Koelblen T, Bergé C, Cherrier MV, Brillet K, Jimenez-Soto L, Ballut L, Takagi J, Montserret R, Rousselle P, Fischer W, Haas R, Fronzes R, Terradot L. FEBS J. 284 4143-4157 (2017)
  10. Genetic variants of Helicobacter pylori type IV secretion system components CagL and CagI and their association with clinical outcomes. Ogawa H, Iwamoto A, Tanahashi T, Okada R, Yamamoto K, Nishiumi S, Yoshida M, Azuma T. Gut Pathog 9 21 (2017)
  11. Crystal structure of CagL from Helicobacter pylori K74 strain. Choi JM, Choi YH, Sudhanva MS, Devakumar S, Lee KH, Cha JH, Lee SH. Biochem. Biophys. Res. Commun. 460 964-970 (2015)
  12. Helicobacter pylori cagL amino acid polymorphism D58E59 pave the way toward peptic ulcer disease while N58E59 is associated with gastric cancer in north of Iran. Cherati MR, Shokri-Shirvani J, Karkhah A, Rajabnia R, Nouri HR, Nouri HR. Microb. Pathog. 107 413-418 (2017)
  13. A C-Terminal Coiled-Coil Region of CagL is Responsible for Helicobacter Pylori-Induced Il-8 Expression. Wiedemann T, Hofbaur S, Loell E, Rieder G. Eur J Microbiol Immunol (Bp) 6 186-196 (2016)
  14. CagL polymorphisms between East Asian and Western Helicobacter pylori are associated with different abilities to induce IL-8 secretion. Choi YH, Lai J, Kim MA, Kim A, Kim J, Su H, Ge L, Cha JH. J Microbiol 59 763-770 (2021)
  15. Crystal structure of an engineered YopM-InlB hybrid protein. Breitsprecher D, Gherardi E, Bleymüller WM, Niemann HH. BMC Struct. Biol. 14 12 (2014)
  16. Expression of CEACAM1 or CEACAM5 in AZ-521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori. Tegtmeyer N, Harrer A, Schmitt V, Singer BB, Backert S. Cell. Microbiol. 21 e12965 (2019)
  17. CagL polymorphisms D58/K59 are predominant in Helicobacter pylori strains isolated from Mexican patients with chronic gastritis. Román-Román A, Martínez-Santos VI, Castañón-Sánchez CA, Albañil-Muñoz AJ, González-Mendoza P, Soto-Flores DG, Martínez-Carrillo DN, Fernández-Tilapa G. Gut Pathog 11 5 (2019)
  18. Designed Ankyrin Repeat Proteins provide insights into the structure and function of CagI and are potent inhibitors of CagA translocation by the Helicobacter pylori type IV secretion system. Blanc M, Lettl C, Guérin J, Vieille A, Furler S, Briand-Schumacher S, Dreier B, Bergé C, Plückthun A, Vadon-Le Goff S, Fronzes R, Rousselle P, Fischer W, Terradot L. PLoS Pathog 19 e1011368 (2023)
  19. Differences in amino acid frequency in CagA and VacA sequences of Helicobacter pylori distinguish gastric cancer from gastric MALT lymphoma. Hashinaga M, Suzuki R, Akada J, Matsumoto T, Kido Y, Okimoto T, Kodama M, Murakami K, Yamaoka Y. Gut Pathog 8 54 (2016)
  20. Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases. Yadegar A, Mohabati Mobarez A, Zali MR. Cancer Med 8 1619-1632 (2019)
  21. Identification of Pri-miRNA Stem-Loop Interacting Proteins in Plants Using a Modified Version of the Csy4 CRISPR Endonuclease. Lüders J, Winkel AR, Reichel M, Bitterer VW, Scheibe M, Widmann C, Butter F, Köster T. Int J Mol Sci 23 8961 (2022)
  22. Importance of cortactin for efficient epithelial NF-ĸB activation by Helicobacter pylori, Salmonella enterica and Pseudomonas aeruginosa, but not Campylobacter spp. Tegtmeyer N, Soltan Esmaeili D, Sharafutdinov I, Knorr J, Naumann M, Alter T, Backert S. Eur J Microbiol Immunol (Bp) 11 95-103 (2022)
  23. Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation. Zhao Q, Busch B, Jiménez-Soto LF, Ishikawa-Ankerhold H, Massberg S, Terradot L, Fischer W, Haas R. PLoS Pathog. 14 e1007359 (2018)
  24. New CagL Amino Acid Polymorphism Patterns of Helicobacter pylori in Peptic Ulcer and Non-Ulcer Dyspepsia. Caliskan R, Polat Sari S, Ercan B, Peker KD, Omac Sonmez M, Akgul O, Sapmaz B, Soylu A, Adas GT, Oner YA, Yuksel Mayda P. Medicina (Kaunas) 58 1738 (2022)
  25. The Relationship between Gastroduodenal Pathologies and Helicobacter pylori cagL (Cytotoxin-Associated Gene L) Polymorphism. Özbey D, Demiryas S, Akkuş S, Kepil N, Dinç HÖ, Gareayaghi N, Demirci M, Kurt EA, Uysal Ö, Sarıbaş S, Tokman HB, Kocazeybek B. Turk J Gastroenterol 34 346-355 (2023)
  26. Type IV secretion of Helicobacter pylori CagA into oral epithelial cells is prevented by the absence of CEACAM receptor expression. Tegtmeyer N, Ghete TD, Schmitt V, Remmerbach T, Cortes MCC, Bondoc EM, Graf HL, Singer BB, Hirsch C, Backert S. Gut Pathog 12 25 (2020)


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