Biology:Cathepsin Z

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation.

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 carboxy-monopeptidase and carboxy-dipeptidase 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.

Further reading

• "Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions". FEBS Letters 434 (1–2): 135–9. August 1998. doi:10.1016/S0014-5793(98)00964-8. PMID 9738465. 
• "Identification and molecular cloning of cathepsin P, a novel human putative cysteine protease of the papain family". Pflügers Archiv 439 (3 Suppl): R116–8. 2000. doi:10.1007/s004240000112. PMID 10653162. 
• "Tissue expression and immunolocalization of a novel human cathepsin P". Pflügers Archiv 439 (3 Suppl): R119–21. 2000. doi:10.1007/s004240000113. PMID 10653163. 
• "Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine". Journal of Molecular Biology 295 (4): 939–51. January 2000. doi:10.1006/jmbi.1999.3410. PMID 10656802. 
• "Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease". Structure 8 (3): 305–13. March 2000. doi:10.1016/S0969-2126(00)00108-8. PMID 10745011. 
• "Murine and human cathepsin Z: cDNA-cloning, characterization of the genes and chromosomal localization". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1491 (1–3): 93–106. April 2000. doi:10.1016/s0167-4781(00)00021-x. PMID 10760573. 
• "Characterization of TH1 and CTSZ, two non-imprinted genes downstream of GNAS1 in chromosome 20q13". Human Genetics 107 (2): 165–75. August 2000. doi:10.1007/s004390000344. PMID 11030415. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. November 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports 1 (3): 287–92. September 2000. doi:10.1093/embo-reports/kvd058. PMID 11256614. 
• "From ORFeome to biology: a functional genomics pipeline". Genome Research 14 (10B): 2136–44. October 2004. doi:10.1101/gr.2576704. PMID 15489336. 
• "Defining the substrate specificity of mouse cathepsin P". Archives of Biochemistry and Biophysics 435 (1): 190–6. March 2005. doi:10.1016/j.abb.2004.12.007. PMID 15680921. 
• "The LIFEdb database in 2006". Nucleic Acids Research 34 (Database issue): D415–8. January 2006. doi:10.1093/nar/gkj139. PMID 16381901. 
• "RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties". The Journal of Biological Chemistry 281 (51): 39588–97. December 2006. doi:10.1074/jbc.M513439200. PMID 17065156. 

External links

• The MEROPS online database for peptidases and their inhibitors: C01.013
• Overview of all the structural information available in the PDB for UniProt: Q9UBR2 (Cathepsin Z) at the PDBe-KB.