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 (Aug 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters. 369 (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 (Aug 1998). "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships". European Journal of Biochemistry / FEBS. 255 (3): 527–34. doi:10.1046/j.1432-1327.1998.2550527.x. PMID9738890.
^Wani AA, Devkar N, Patole MS, Shouche YS (Feb 2006). "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". Journal of Periodontology. 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 (May 2006). "A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity". Blood. 107 (9): 3665–8. doi:10.1182/blood-2005-03-1140. PMID16410452.
McGuire MJ, Lipsky PE, Thiele DL (Jun 1992). "Purification and characterization of dipeptidyl peptidase I from human spleen". Archives of Biochemistry and Biophysics. 295 (2): 280–8. doi:10.1016/0003-9861(92)90519-3. PMID1586157.
Paris A, Strukelj B, Pungercar J, Renko M, Dolenc I, Turk V (Aug 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters. 369 (2-3): 326–30. doi:10.1016/0014-5793(95)00777-7. PMID7649281.
Dolenc I, Turk B, Pungercic G, Ritonja A, Turk V (Sep 1995). "Oligomeric structure and substrate induced inhibition of human cathepsin C". The Journal of Biological Chemistry. 270 (37): 21626–31. doi:10.1074/jbc.270.37.21626. PMID7665576.
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Rao NV, Rao GV, Hoidal JR (Apr 1997). "Human dipeptidyl-peptidase I. Gene characterization, localization, and expression". The Journal of Biological Chemistry. 272 (15): 10260–5. doi:10.1074/jbc.272.15.10260. PMID9092576.
Fischer J, Blanchet-Bardon C, Prud'homme JF, Pavek S, Steijlen PM, Dubertret L, Weissenbach J (1997). "Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region". European Journal of Human Genetics. 5 (3): 156–60. PMID9272739.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Cigić B, Krizaj I, Kralj B, Turk V, Pain RH (Jan 1998). "Stoichiometry and heterogeneity of the pro-region chain in tetrameric human cathepsin C". Biochimica et Biophysica Acta. 1382 (1): 143–50. doi:10.1016/S0167-4838(97)00173-8. PMID9507095.
Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS (Dec 1999). "Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis". Nature Genetics. 23 (4): 421–4. doi:10.1038/70525. PMID10581027.
Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, Watanabe M, Komatsu T, Ota T, Isogai T, Suyama A, Sugano S (Mar 2000). "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics. 64 (3): 286–97. doi:10.1006/geno.2000.6076. PMID10756096.
Cigić B, Dahl SW, Pain RH (Oct 2000). "The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme". Biochemistry. 39 (40): 12382–90. doi:10.1021/bi0008837. PMID11015218.
Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, Hashimoto I, Uitto J (Feb 2001). "Papillon-Lefèvre syndrome: mutations and polymorphisms in the cathepsin C gene". The Journal of Investigative Dermatology. 116 (2): 339–43. doi:10.1046/j.1523-1747.2001.01244.x. PMID11180012.