Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins αVβ3 and α5β1

Abstract

The human pathogen Helicobacter pylori that may cause different gastric diseases exploits integrins for infection of gastric cells. The H. pylori protein CagL present on the outer region of the type IV secretion pilus contains an RGD sequence (-Arg-Gly-Asp-) that enables binding to cells presenting integrins α5β1 and αVβ3. This interaction can be inhibited with conformationally designed cyclic RGD peptides derived from the CagL epitope -Ala-Leu-Arg-Gly-Asp-Leu-Ala-. The inhibition of the CagL-αVβ3 interaction by different RGD peptides strongly suggests the importance of the RGD motif for CagL binding. CagL point mutants (RAD, RGA) show decreased affinity to integrin αVβ3. Furthermore, structure-activity relationship studies with cyclic RGD peptides in a spatial screening approach show the distinct influence of the three-dimensional arrangement of RGD motif on the ability to interfere with this interaction. Resulting from these studies, similar structural requirements for the CagL epitope as previously suggested for other ligands of integrin αVβ3 are proposed.

Crystal structure of CagL from Helicobacter pylori K74 strain

“…Further importance of CagL RGD-mediated integrin binding was reported using a cyclic RGD peptide, which 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 interferes with binding of Hp CagL to integrins, such as aVb3 [15].…”

Integrin Engagement by the Helical RGD Motif of the Helicobacter pylori CagL Protein Is Regulated by pH-induced Displacement of a Neighboring Helix

“…These data indicate that CagL undergoes significant conformational changes in solution in response to pH that are equivalent to those observed in the crystal structures. CagL Adherence to Host Cells and Functional Consequences Are pH-dependent-Numerous studies have shown that CagL binds to human gastric epithelial cells dependent on its RGD motif to cell surface integrins ␣ 5 ␤ 1 , ␣ V ␤ 5 , and ␣ V ␤ 3 and that this interaction is an essential step for the delivery of the effector protein CagA into host cells (8,19,20). RGD motifs are common to many proteins that bind integrins and, prior to the originally published CagL structure (23), were found exclusively in loop sequences.…”

Signal transduction ofHelicobacter pyloriduring interaction with host cell protein receptors of epithelial and immune cells

“…This interaction can be inhibited with conformational designed cyclic RGD peptides derived from the CagL epitope ALRGDLA (-Ala-Leu-ArgGly-Asp-Leu-Ala-). 92 Inhibition of the CagL-α v β 3 interaction by different RGD peptides verified the importance of the RGD motif for CagL binding capabilities. In agreement with these findings, CagL RAD and CagL RGA point mutants exhibited decreased affinity to integrin α v β 3 .…”

“…In agreement with these findings, CagL RAD and CagL RGA point mutants exhibited decreased affinity to integrin α v β 3 . 92 Moreover, structureactivity relationship studies with cyclic RGD peptides in a spatial screening approach revealed a distinct influence of the threedimensional arrangement in the RGD motif on the ability to interfere with this interaction, however, an H. pylori-triggered downstream signaling cascade is yet unknown for integrin α v β 3 . Nevertheless, the above studies strongly suggest that H. pylori can target an array of at least three integrin members on epithelial cells for different purposes.…”