uncharacterized subgroup of the Peptidase C25 family N-terminal domain
Domains in this subgroup are uncharacterized members of the Peptidase family C25 N-terminal domain family. Peptidases family C25 are a unique class of cysteine proteases, exemplified by gingipain, which is produced by Porphyromonas gingivalis. P. gingivalis is one of the primary gram-negative pathogens that causes periodontitis, a disease that is also associated with other diseases such as diabetes and cardiovascular disease. Gingipains are a group of extracellular Arg- and Lys-specific proteinases called Arg-gingipain (Rgp) and Lys-gingipain (Kgp); RgpA and RgpB are homologous Arg-specific gingipains encoded by two closely related genes, rgpA and rgpB, while Lys-specific gingipain is encoded by the single kgp gene. Mutant studies have shown that, among the large quantities of proteolytic enzymes produced by P. gingivalis, these three proteases are major virulence factors of this bacterium. All three genes encode an N-terminal pre-pro fragment, followed by the protease domain; however, rgpA and kgp also encode additional C-terminal HA (hemaglutinin/adhesion) subunits which consist of several sequence-related adhesion domains. Although unique, their cysteine protease active site residues (His and Cys) forming the catalytic dyad are well-conserved, cleaving the C-terminal peptide bond with Arg or Lys residues. Gingipains are evolutionarily related to other highly specific proteases including caspases, clostripain, legumains, and separase. Gingipains function by dysregulating host defense and inflammatory responses, and degrading host proteins, e.g. tissue, cells, matrix, plasma and immunological proteins. They are proposed to enhance gingival crevicular fluid (GCF) production through activation of the kallikrein/kinin pathways, thus increasing vascular permeability and causing gingival inflammation, a distinctive feature of periodontitis. RgpA and RgpB are also able to cleave and activate coagulation factors IX and X in order to activate prothrombin to produce thrombin, which in turn increases production of GCF. The gingipains also play a pivotal role in the survival of P. gingivalis in the host by attacking the host defense system through cleavage of several immunological molecules, while at the same time evading the host-immune response by dysregulating the cytokine network.
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