Page 67 - Read Online

Page 2 of 17 Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09

[1]
animal tissues . It belongs to the papain-like family of cysteine peptidases (PLPs), which is classified as
[2]
family C1, clan CA in the MEROPS database of peptidases, inhibitors, and substrates . It is found in
animals and several other eukaryote lineages . In humans, it is encoded by the CATC gene located at
[3,4]
chromosomal location 11q14.2. It is ubiquitously expressed in humans and other mammals and is a
[5]
unique peptidase both in terms of its biochemical properties and its specific physiological and pathological
[3]
functions . It plays a pivotal role in the activation of effector serine peptidases in immune cells such as
neutrophils, cytotoxic T lymphocytes, and others. This led to the establishment of cathepsin C as a
promising target for the treatment of inflammatory diseases that are characterized by excessive activation of
cells of the immune system . Numerous more or less successful inhibitors of cathepsin C have been
[6]
[6]
synthesized and evaluated to date . The most advanced inhibitor, brensocatib (Insmed, Inc, USA), is
currently undergoing a phase 3 clinical trial for the treatment of non-cystic fibrosis bronchiectasis .
[7]
Furthermore, cathepsin C is well-known for the fact that mutations in the CATC gene cause the recessive
hereditary diseases called Papillon-Lefèvre syndrome and Haim-Munk syndrome [8-10] , highlighting the
systemic effects of cathepsin C deficiency. Symptoms include early periodontitis, pathological thickening of
the skin on the palms and feet, and increased susceptibility to infection . Apart from these, many other
[11]
(patho)physiological functions have been attributed to cathepsin C in recent decades.

In this review, we summarize the current state of the art on the structural and functional properties of
cathepsin C, its processing and trafficking in the cell, and its roles in human physiology and pathology. As
this review is part of the special issue “Neutrophil Serine Proteases in Rare Diseases”, the primary focus is
on its roles in the immune system, particularly in neutrophils. In the end, we also provide an overview of
current and emerging strategies for the pharmacological targeting of cathepsin C in human disease.

STRUCTURE AND FUNCTION OF CATHEPSIN C
Many expert reviews on the structural and functional properties of PLPs in general are available, e.g.,
references [3,12] , and the reader is advised to refer to these for more in-depth information on this topic.
Herein, we are focusing on cathepsin C and its specific structural and functional properties. Like other
members of the PLP family, cathepsin C is synthesized as an inactive precursor called procathepsin C. Its
active site contains a Cys-His catalytic dyad that forms a thiolate-imidazolium ion pair (residues Cys234 and
His381 according to procathepsin C numbering). What distinguishes it from other PLPs is the additional
exclusion domain, the fold of which is similar to that of metalloprotease inhibitors . The exclusion domain
[13]
is located at the N-terminus of procathepsin C and is separated from the catalytic peptidase domain by the
propeptide [Figure 1A]. Upon activation, the propeptide (residues Ala111 through His206) is removed,
leaving the exclusion domain non-covalently bound to the peptidase domain, which in turn is cleaved into a
heavy chain and a light chain by cleavage between Arg370 and Asp371 . As its name suggests, the crucial
[13]
functional role of the exclusion domain is that it sterically hinders access to the active site beyond site S2
[Figure 1B], making cathepsin C a dipeptidyl-peptidase, i.e., an exopeptidase that cleaves dipeptides of the
N-termini of its substrates. Moreover, the side chain of residue Asp1 interacts with the N-terminus of the
[13]
substrate and stabilizes its binding . The selectivity of the S2 binding site, which is the primary specificity
determinant of PLPs, is dominated by two negative charges, namely the aforementioned side chain of
residue Asp1 at the entrance of the pocket and a chloride ion at the bottom of a deep hydrophobic pocket
[Figure 1C]. The latter is required for enzyme activity and is another distinguishing feature of cathepsin C
that sets it apart from other PLPs [13,14] . In our recent evolutionary analysis of cathepsin C, we found that
residue Asp1 is strictly conserved in all cathepsin C enzymes throughout the phylogenetic tree, suggesting
that dipeptidyl-peptidase activity is the conserved enzymatic activity of these enzymes in all species . The
[4]
substrate binding sites S1, S1', and S2' do not have any special features compared to other members of the
family . Cathepsin C has a relatively broad substrate specificity [16-19] and usually acts by the stepwise
[15]