Cathepsin Z

Structure

Gene

The CTSZ gene is located at 20q13.32 on chromosome 20, consisting of 6 exons. At least two transcript variants of this gene have been found, but the full-length nature of only one of them has been determined.

Protein

Cathepsin Z is characterized by an unusual and unique 3-amino acid insertion in the highly conserved region between the glutamine of the putative oxynion hole and the active site cysteine. The pro-region of cathepsin Z shares no significant similarity with other cathepsin family sequences. It contains only 41 amino acid residues without the conserved motif of ERFNIN or GNFD found in other cysteine proteinases. Besides, the proregion sequence contains no lysine residue.

Function

The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both and activities. Up to date, eleven human cysteine proteinases have been identified, including cathepsin B, cathepsin C, cathepsin F, cathepsin H, cathepsin K, cathepsin L, cathepsin L2 or V, cathepsin O, cathepsin S, cathepsin Z, and cathepsin W. These cysteine proteinases belong to the papain family and represent a major component of the lysosomal proteolytic system. In addition to playing a critical role in protein degradation and turnover, these proteinases appear to play an extracellular role in a number of normal and pathological conditions. The human cathepsin Z contains distinctive features from other human cysteine proteases. It is an exopeptidase with strict carboxypeptidase activity, while most other cathepsins are endopeptidases. Cathepsin Z has an exposed integrin-binding Arg-Gly-Asp motif within the propeptide of the enzyme, through which cathepsin Z has been shown to interact with several integrins during normal homeostasis, immune processes and cancer. It is also shown to bind cell surface heparin sulphate proteoglycans, indicating possible functions in cellular adhesion and phagocytosis.

Clinical significance

This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis. For instance, cathepsin Z promotes invasion and migration via a noncatalytic mechanism, suggesting multiple modes of cell invasion may be involved in cancer malignancy. Cathepsin Z is also reported to have a protective, but not proteolytic, function in inflammatory gastric disease. It is reported in another study that cathepsin Z may be responsible for dopamine neuron death and thus involved in the pathogenic cascade event. Single-nucleotide polymorphism in CTSZ is found associated with tuberculosis susceptibility, indicating that the pathways involving this protein could yield novel therapies for tuberculosis.

Interactions

Cathepsin Z has been shown to interact with the following proteins: CEP55, FBXO6, KIFC1, KRT40, KRTAP5-9, KRTAP5-9, LYPLAL1, MID2, MSN, MTUS2, NOTCH2NL, PLK2, PLSCR1, SGOL2, and SPRED2.

Cathepsin Z has also been found to interact with:

• Integrin,
• PRLP0, and
• γ-Enolase.

References

References

1. (July 1998). "Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location". The Journal of Biological Chemistry.
2. "Entrez Gene: CTSZ cathepsin Z".
3. (January 2012). "Cysteine cathepsins: from structure, function and regulation to new frontiers". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics.
4. (September 1999). "Human cathepsin X: A cysteine protease with unique carboxypeptidase activity". Biochemistry.
5. (August 1998). "Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions". FEBS Letters.
6. (December 2006). "RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties". The Journal of Biological Chemistry.
7. (April–June 2009). "The role of cathepsin X in cell signaling". Cell Adhesion & Migration.
8. (November 2008). "Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X". Journal of Leukocyte Biology.
9. (October 2014). "Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix". Genes & Development.
10. (January 2015). "Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer". Pathology, Research and Practice.
11. (2013). "Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice". PLOS ONE.
12. (July 2014). "Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells". Neuropharmacology.
13. (June 2011). "Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility". European Journal of Human Genetics.
14. "CTSZ interaction network". [[BioGRID]].
15. (August 2013). "Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X". Aging Cell.