Structural and functional aspects of the Helicobacter pylori secretome

Abstract

Proteins secreted by Helicobacter pylori (H. pylori), an important human pathogen responsible for severe gastric diseases, are reviewed from the point of view of their biochemical characterization, both functional and structural. Despite the vast amount of experimental data available on the proteins secreted by this bacterium, the precise size of the secretome remains unknown. In this review, we consider as secreted both proteins that contain a secretion signal for the periplasm and proteins that have been detected in the external medium in in vitro experiments. In this way, H. pylori's secretome appears to be composed of slightly more than 160 proteins, but this number must be considered very cautiously, not only because the definition of secretome itself is ambiguous but also because the included proteins were observed as secreted in in vitro experiments that were not representative of the environmental situation in vivo. The proteins that appear to be secreted can be grouped into different classes: enzymes (48 proteins), outer membrane proteins (43), components of flagella (11), members of the cytotoxic-associated genes pathogenicity island or other toxins (8 and 5, respectively), binding and transport proteins (9), and others (11). A final group, which includes 28 members, is represented by hypothetical uncharacterized proteins. Despite the large amount of data accumulated on the H. pylori secretome, a considerable amount of work remains to reach a full comprehension of the system at the molecular level.

Keywords: Helicobacter pylori; Periplasmic space; Secreted proteins; Secretion signal; Secretome.

Figure 1

Cartoon view of the superimposed Cα traces of HpaA paralogs. HP0410 dimer (3bgh, green) and HP0492 dimer (2i9i, red and light blue). Cα root mean square deviation between equivalent atoms corresponds to 2.4 Å.

Figure 2

Cartoon model of Cag proteins. A: The N-terminal portion of cytotoxic-associated genes, CagA, the effector protein injected into the host cell through type IV secretion system. The three domains (residues 24-221, blue; 303-644, yellow; 645-824, salmon; coordinates from PDB 4DVY) are shown in different colors; B: CagD dimer. The two monomers are linked together by a disulfide bridge between the two C-terminal β-strands. Coordinates from PDB 3CWX.

Figure 3

Binding and transport proteins. A: Cartoon model of HP1286 lipocalin dimer. The two monomers, related by a two-fold axis, bind in the inner cavity a molecule of erucamide (silver spheres; PDB 3HPE); B: Nuclear magnetic resonance structure of apo-CopP, a copper binding regulatory protein of 66 amino acid residues (PDB 1YG0).

Figure 4

Toxins. A: Cartoon model of the p55 domain of vacuolating toxin (VacA) (coordinates from PDB 2QV3). The structure is a predominantly right-handed parallel β-helix, and the domain mediates the binding of VacA to the host cell; B: Cartoon model of a truncated form of tumor-necrosis-factor α (TNFα) inducing protein, a virulence factor that enters gastric cells and stimulates both the production of TNFα and the nuclear factor kappa B pathway (coordinates PDB 2WCR).

Figure 5

Redox proteins. A: Space-filling model of the dimer of DsbG (HP0231; PDB 3TDG); B: Cartoon of DsbC (HP0377; Coordinates PDB 4FYC), an enzyme with a thioredoxin-like fold possibly involved in cytochrome c assembly; C: Cartoon of the dimeric Fe-superoxide dismutase (Coordinates PDB 3CEI). The iron ion is represented by a red sphere; D: Dimeric thioredoxin reductase (Coordinates PDB 3ISH). The FAD bound is shown as a ball-and-stick model.

Figure 6

Two examples of solenoid-class proteins. A: HcpB (HP0336, coordinates PDB1KLX); B: HcpC (HP1098, coordinates PDB 1OUV).