A Helical RGD Motif Promoting Cell Adhesion: Crystal Structures of the Helicobacter pylori Type IV Secretion System Pilus Protein CagL

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. •CagL is a four-helix bundle and structurally unrelated to the VirB5 homolog TraC•The CagL RGD motif is surface exposed but distinctly located within a long helix•Adhesion of gastric epithelial cells to CagL strictly depends on the RGD motif•Stabilizing disulfides show that flexibility is essential for CagL function CagL is a specialized adhesin from the T4SS of the human pathogen H. pylori. Barden et al. report on two crystal structures of CagL, revealing the first adhesion-mediating RGD motif embedded in a long α helix, and find that structural flexibility of CagL is a prerequisite for cell adhesion.