Abstract
Cysteine cathepsin C (CatC) is a ubiquitously expressed, lysosomal aminopeptidase involved in the activation of zymogens of immune-cell-associated serine proteinases (elastase, cathepsin G, proteinase 3, neutrophil serine proteinase 4, lymphocyte granzymes, and mast cell chymases). CatC is first synthetized as an inactive zymogen containing an intramolecular chain propeptide, the dimeric form of which is processed into the mature tetrameric form by proteolytic cleavages. A molecular modeling analysis of proCatC indicated that its propeptide displayed a similar fold to those of other lysosomal cysteine cathepsins, and could be involved in dimer formation. Our in vitro experiments revealed that human proCatC was processed and activated by CatF, CatK, and CatV in two consecutive steps of maturation, as reported for CatL and CatS previously. The unique positioning of the propeptide domains in the proCatC dimer complex allows this order of cleavages to be understood. The missense mutation Leu172Pro within the propeptide region associated with the Papillon–Lefèvre and Haim–Munk syndrome altered the proform stability as well as the maturation of the recombinant Leu172Pro proform.
Highlights
As with other lysosomal cysteine cathepsins, Cathepsin C (CatC) is expressed as an inactive zymogen
Maturation of the proCatC dimer is achieved by the proteolytic removal of its internal propeptide segment and cleavage of the catalytic domain into a heavy and light chain
The 3D zymogen structures of other cysteine cathepsins show that their propeptide segments fold on the surface of the catalytic domain in an extended conformation running through the active site cleft in the opposite direction to the substrate, blocking access to the active site [2,22,23]
Summary
Eleven cysteine cathepsins (B, C, F, H, L, S, K (a.k.a. O2), O, V, X (a.k.a. Z/P) and W) that are related to papain (clan CA, family C1, subfamily C1A; see MEROPS: the peptidase database (Release 12.1): http:// merops.sanger.ac.uk) have been identified and characterized to date in humans [1,2,3]. Z/P) and W) that are related to papain (clan CA, family C1, subfamily C1A; see MEROPS: the peptidase database (Release 12.1): http:// merops.sanger.ac.uk) have been identified and characterized to date in humans [1,2,3] They all are lysosomal proteinases, which act as house-keeping proteinases involved in bulk protein degradation, and process other endogenous proteins in a relatively specific manner [1,2].
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