| Cathepsin C exclusion domain | |||||||
|---|---|---|---|---|---|---|---|
 re-determination of the native structure of human dipeptidyl peptidase i (cathepsin c) | |||||||
| Identifiers | |||||||
| Symbol | CathepsinC_exc | ||||||
| Pfam | PF08773 | ||||||
| InterPro | IPR014882 | ||||||
| SCOP2 | 1k3b / SCOPe / SUPFAM | ||||||
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Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I or DPP1) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene. [5] [6]
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.
Particularly, it is involved in activation of neutrophil serine proteases (NSPs; i.e., cathepsin G, proteinase 3 and neutrophil elastase) as they are synthesised as inactive proenzymes during neutrophil maturation. Then, they are released during degranulation. [7] [8] Other enzymes activated by cathepsin C are: chymase and tryptase in mast cells and granzymes A and B, cathepsin G, and elastase in lymphocytes and natural killer cells (NK cells). [9]
Overactivation of NSPs causes a cascade of processess that result in excessive lung inflammation and reduced pathogen clearance. They involve reduced secretion of antileukoproteinase, extracellular matrix degradation, activation of IL-1β, IL-8 and TNF-α as well as inhibition of alpha-1 antitrypsin, an enzyme involved in NSP degradation. [8]
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. [10] 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. [11]
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), [12] 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.
Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre disease, [13] [14] an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis.
Inhibition of DPP-I addresses the inflammatory response that is thought to be responsible for one of many aspects of degenerative lung diseases, including bronchiectasis [15] , chronic obstructive pulmonary disease (COPD), asthma and asthma-COPD overlap [16] .
Brensocatib, a DPP-I inhibitor, was approved in 2025 by the FDA [17] and the EMA [18] to treat bronchiectasis.
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