Cathepsin C appears to be a central coordinator for activation of many serine proteases in immune/inflammatory cells.
Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates, except if (i) the amino group of the N-terminus is blocked, (ii) the site of cleavage is on either side of a proline residue, (iii) the N-terminal residue is lysine or arginine, or (iv) the structure of the peptide or protein prevents further digestion from the N-terminus.
The cDNAs encoding rat, human, murine, bovine, dog and two Schistosome cathepsin Cs have been cloned and sequenced and show that the enzyme is highly conserved. The human and rat cathepsin C cDNAs encode precursors (prepro-cathepsin C) comprising signal peptides of 24 residues, pro-regions of 205 (rat cathepsin C) or 206 (human cathepsin C) residues and catalytic domains of 233 residues which contain the catalytic residues and are 30-40% identical to the mature amino acid sequences of papain and a number of other cathepsins including cathepsins, B, H, K, L, and S.
The translated prepro-cathepsin C is processed into the mature form by at least four cleavages of the polypeptide chain. The signal peptide is removed during translocation or secretion of the pro-enzyme (pro-cathepsin C) and a large N-terminal proregion fragment (also known as the exclusion domain), which is retained in the mature enzyme, is separated from the catalytic domain by excision of a minor C-terminal part of the pro-region, called the activation peptide. A heavy chain of about 164 residues and a light chain of about 69 residues are generated by cleavage of the catalytic domain.
Unlike the other members of the papain family, mature cathepsin C consists of four subunits, each composed of the N-terminal proregion fragment, the heavy chain and the light chain. Both the pro-region fragment and the heavy chain are glycosylated.
Cathepsin C functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. In many inflammatory diseases, such as Rheumatoid Arthritis, Chronic Obstructive Pulmonary Disease (COPD), Inflammatory Bowel Disease, Asthma, Sepsis and Cystic Fibrosis, a significant part of the pathogenesis is caused by increased activity of some of these inflammatory proteases. Once activated by cathepsin C, the proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.
^Paris A, Strukelj B, Pungercar J, Renko M, Dolenc I, Turk V (August 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters369 (2–3): 326–30. doi:10.1016/0014-5793(95)00777-7. PMID7649281.
^Hola-Jamriska L, Tort JF, Dalton JP, Day SR, Fan J, Aaskov J, Brindley PJ (August 1998). "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships". European Journal of Biochemistry / FEBS255 (3): 527–34. doi:10.1046/j.1432-1327.1998.2550527.x. PMID9738890.
^Wani AA, Devkar N, Patole MS, Shouche YS (2006). "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". J. Periodontol.77 (2): 233–7. doi:10.1902/jop.2006.050124. PMID16460249.
^Meade JL, de Wynter EA, Brett P, Sharif SM, Woods CG, Markham AF, Cook GP (2006). "A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity". Blood107 (9): 3665–3668. doi:10.1182/blood-2005-03-1140. PMID16410452.
Paris A, Strukelj B, Pungercar J et al. (1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Lett.369 (2–3): 326–30. doi:10.1016/0014-5793(95)00777-7. PMID7649281.CS1 maint: Explicit use of et al. (link)
Dolenc I, Turk B, Pungercic G et al. (1995). "Oligomeric structure and substrate induced inhibition of human cathepsin C". J. Biol. Chem.270 (37): 21626–31. doi:10.1074/jbc.270.37.21626. PMID7665576.CS1 maint: Explicit use of et al. (link)
Rao NV, Rao GV, Hoidal JR (1997). "Human dipeptidyl-peptidase I. Gene characterization, localization, and expression". J. Biol. Chem.272 (15): 10260–5. doi:10.1074/jbc.272.15.10260. PMID9092576.
Fischer J, Blanchet-Bardon C, Prud'homme JF et al. (1997). "Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region". Eur. J. Hum. Genet.5 (3): 156–60. PMID9272739.CS1 maint: Explicit use of et al. (link)
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.CS1 maint: Explicit use of et al. (link)
Cigić B, Krizaj I, Kralj B et al. (1998). "Stoichiometry and heterogeneity of the pro-region chain in tetrameric human cathepsin C". Biochim. Biophys. Acta1382 (1): 143–50. doi:10.1016/S0167-4838(97)00173-8. PMID9507095.CS1 maint: Explicit use of et al. (link)
Toomes C, James J, Wood AJ et al. (1999). "Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis". Nat. Genet.23 (4): 421–4. doi:10.1038/70525. PMID10581027.CS1 maint: Explicit use of et al. (link)
Suzuki Y, Ishihara D, Sasaki M et al. (2000). "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics64 (3): 286–97. doi:10.1006/geno.2000.6076. PMID10756096.CS1 maint: Explicit use of et al. (link)
Cigić B, Dahl SW, Pain RH (2000). "The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme". Biochemistry39 (40): 12382–90. doi:10.1021/bi0008837. PMID11015218.