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Review
, 54 (1), 15-44

Dichotomy of Gingipains Action as Virulence Factors: From Cleaving Substrates With the Precision of a Surgeon's Knife to a Meat Chopper-Like Brutal Degradation of Proteins

Review

Dichotomy of Gingipains Action as Virulence Factors: From Cleaving Substrates With the Precision of a Surgeon's Knife to a Meat Chopper-Like Brutal Degradation of Proteins

Yonghua Guo et al. Periodontol 2000.

Figures

Fig. 1
Fig. 1
Schematic diagram of discrete steps in gingipain secretion, processing, posttranslational maturation, and assembly of extracellular gingipain complexes. Western blot analysis (upper corners) of the whole culture of P. gingivalis strain HG66 and W83 using anti-RgpB mAb illustrates the difference in the molecular mass between soluble and membrane-attached RgpB. [1] Gingipain genes are translated into a polypeptide chain composed of the classical signal peptide (triangle), a propeptide, a catalytic domain, an Ig-like domain, a hemagglutinin-adhesin domain (missing in RgpB) and a C-terminal domain. Black bars in Kgp/RgpA denote oligomerization motifs involved in non-covalent association of individual domains of the HRgpA/Kgp complex (200). [2] Nascent translation products are translocated across the inner membrane (IM) by the Sec system with simultaneous cleavage of the signal peptide. [3] In the periplasm, pro-RgpB undergoes three steps of sequential processing (from a to c, open arrows). First N-terminal propeptide is cleaved off in two steps (a and b) then the C-terminal domain is removed (c). Each processing step requires the previous step leading to incremental enhancement of the activity in a stepwise manner (123). The intact C-terminal domain, prior to its processing, is essential for RgpB maturation and secretion (136, 189). In strain HG66, non-glycosylated RgpB is released into extracellular milieu in the soluble form; in all other strains, RgpB is glycosylated and remain bound to the cell-surface. Small circles indicate lipopolysaccharide-like glycan moieties for membrane anchorage. [4] RgpA and Kgp processing is more complicated than that of RgpB. In addition to the propeptide removal, several cleavages within hemagglutinin-adhesin (HA) (open arrows) liberate individual functional domains which remain non-covalently associated. Concurrent with the proteolytic processing or the outer membrane (OM) translocation, a glycan moiety is attached to the HA4 domain for membrane anchorage. [5] Gingipains traverse the outer membrane using a unique secretion pathway apparently via a novel outer membrane translocase apparatus (185).
Fig. 2
Fig. 2
Activation pathways of the complement system and points of gingipain intervention. Complement is initiated by three major pathways. The alternative pathway is triggered due to a failure to appropriately regulate constant low-level spontaneous deposition of activated C3 on foreign surfaces. Spontaneously hydrolyzed C3 forms a complex with factor B (fB) leading to formation of the initial alternative pathway C3 convertase (C3bBb). The lectin pathway is initiated by the binding of mannan binding lectin (MBL) to mannose residues on the surface of microorganisms which activates mannan-binding lectin serine proteases (MASP), which then cleave C4 and C2. The classical pathway is activated when antibodies bind to their corresponding antigen and serine proteases (C1s and C1r) in C1 complex are activated which then cleave C4 and C2. As a result, in both pathways the same C3 convertase (C4bC2b) is formed. All three pathways converge at a central step, involving activation of the third component of complement (C3) leading to the generation of the anaphylatoxin C3a and opsonins C3b and iC3b. In the terminal pathway, C5b initiates the assembly of the C5b–9 membrane attack complex (MAC), which in turn induces microbial cell lysis. Host surfaces are protected from spontaneous complement activation by complement regulators acting at several stages of complement activation pathway (black end lines). The complement regulators are either cell-surface associated proteins, such as CD35 (Complement Receptor 1, CR1), CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF) and CD59 or soluble regulators circulating in blood, including factor H (FH), factor I (FI), C4 binding protein (C4BP), S-protein (vitronectin), and SP-40 (clusterin) (245). Targets for gingipain attack are depicted by red scissors resulting either in the inhibition of the pathway (red end lines) or stimulation of the pathway (thin red arrows).
Fig. 3
Fig. 3
Scheme of the signaling via protease activated receptors (PAR) and cell in the periodontium affected by the gingipain-exerted PAR activation. The inactive status of PARs is associated with a hidden N-terminal-tethered ligand sequence. The tethered ligand part cannot interact with the body of the receptor until it is cleaved off at peptide bond depicted by scissors. Gingipains via cleaving these bonds in different PAR receptors activate signaling pathways in various cell types leading to large variety of pathophysiological responses (for details see Table 3).

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