Cathepsin Z Explained

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene.^{[1] [2]} It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members.^[3] 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.^[2]

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.^[4] 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.^[5] It is an exopeptidase with strict carboxypeptidase activity, while most other cathepsins are endopeptidases.^[3] 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.^{[6] [7] [8] [9]} It is also shown to bind cell surface heparin sulphate proteoglycans, indicating possible functions in cellular adhesion and phagocytosis.^[10]

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.^[9] Cathepsin Z is also reported to have a protective, but not proteolytic, function in inflammatory gastric disease.^[11] It is reported in another study that cathepsin Z may be responsible for dopamine neuron death and thus involved in the pathogenic cascade event.^[12] Single-nucleotide polymorphism in CTSZ is found associated with tuberculosis susceptibility, indicating that the pathways involving this protein could yield novel therapies for tuberculosis.^[13]

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.^[14]

Cathepsin Z has also been found to interact with:

• Integrin,^[9]
• PRLP0,^[10] and
• γ-Enolase.^[15]

Further reading

• Nägler DK, Ménard R . 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 . 9738465 . 10.1016/S0014-5793(98)00964-8 . 22899822 . free .
• Pungercar J, Ivanovski G . 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 . 10653162 . 10.1007/s004240000112 . 22775842 .
• Pungercar J, Viyjak A, Ivanovski G, Krizaj I . Tissue expression and immunolocalization of a novel human cathepsin P . Pflügers Archiv . 439 . 3 Suppl . R119–21 . 2000 . 10653163 . 10.1007/s004240000113 . 22728027 .
• Sivaraman J, Nägler DK, Zhang R, Ménard R, Cygler M . 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 . 10656802 . 10.1006/jmbi.1999.3410 .
• Guncar G, Klemencic I, Turk B, Turk V, Karaoglanovic-Carmona A, Juliano L, Turk D . 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 . 10745011 . 10.1016/S0969-2126(00)00108-8 . free .
• Deussing J, von Olshausen I, Peters C . 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 . 10760573 . 10.1016/s0167-4781(00)00021-x .
• Bonthron DT, Hayward BE, Moran V, Strain L . Characterization of TH1 and CTSZ, two non-imprinted genes downstream of GNAS1 in chromosome 20q13 . Human Genetics . 107 . 2 . 165–75 . August 2000 . 11030415 . 10.1007/s004390000344 . 25570066 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Puzer L, Barros NM, Oliveira V, Juliano MA, Lu G, Hassanein M, Juliano L, Mason RW, Carmona AK . Defining the substrate specificity of mouse cathepsin P . Archives of Biochemistry and Biophysics . 435 . 1 . 190–6 . March 2005 . 15680921 . 10.1016/j.abb.2004.12.007 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–8 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK . RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties . The Journal of Biological Chemistry . 281 . 51 . 39588–97 . December 2006 . 17065156 . 10.1074/jbc.M513439200 . free .

External links

• The MEROPS online database for peptidases and their inhibitors: C01.013

Notes and References

1. Santamaría I, Velasco G, Pendás AM, Fueyo A, López-Otín C . Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location . The Journal of Biological Chemistry . 273 . 27 . 16816–23 . July 1998 . 9642240 . 10.1074/jbc.273.27.16816 . free .
2. Web site: Entrez Gene: CTSZ cathepsin Z.
3. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D . Cysteine cathepsins: from structure, function and regulation to new frontiers . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1824 . 1 . 68–88 . January 2012 . 22024571 . 10.1016/j.bbapap.2011.10.002 . 7105208 . free .
4. Nägler DK, Zhang R, Tam W, Sulea T, Purisima EO, Ménard R . Human cathepsin X: A cysteine protease with unique carboxypeptidase activity . Biochemistry . 38 . 39 . 12648–54 . September 1999 . 10504234 . 10.1021/bi991371z.
5. Nägler DK, Ménard R . 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 . 9738465 . 10.1016/s0014-5793(98)00964-8. 22899822 . free .
6. Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK . RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties . The Journal of Biological Chemistry . 281 . 51 . 39588–97 . December 2006 . 17065156 . 10.1074/jbc.M513439200 . free .
7. Kos J, Jevnikar Z, Obermajer N . The role of cathepsin X in cell signaling . Cell Adhesion & Migration . 3 . 2 . 164–6 . April–June 2009 . 19262176 . 10.4161/cam.3.2.7403 . 2679876.
8. Obermajer N, Svajger U, Bogyo M, Jeras M, Kos J . Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X . Journal of Leukocyte Biology . 84 . 5 . 1306–15 . November 2008 . 18701767 . 10.1189/jlb.0508285 . 3252843.
9. Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA . Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix . Genes & Development . 28 . 19 . 2134–50 . October 2014 . 25274726 . 10.1101/gad.249599.114 . 4180975.
10. Teller A, Jechorek D, Hartig R, Adolf D, Reißig K, Roessner A, Franke S . Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer . Pathology, Research and Practice . 211 . 1 . 62–70 . January 2015 . 25433997 . 10.1016/j.prp.2014.09.005 .
11. Krueger S, Bernhardt A, Kalinski T, Baldensperger M, Zeh M, Teller A, Adolf D, Reinheckel T, Roessner A, Kuester D . Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice . PLOS ONE . 8 . 7 . e70242 . 2013 . 23936173 . 10.1371/journal.pone.0070242 . 3728094. free . 2013PLoSO...870242K .
12. Pišlar AH, Zidar N, Kikelj D, Kos J . Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells . Neuropharmacology . 82 . 121–31 . July 2014 . 23958447 . 10.1016/j.neuropharm.2013.07.040 . 22499368 .
13. Adams LA, Möller M, Nebel A, Schreiber S, van der Merwe L, van Helden PD, Hoal EG . Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility . European Journal of Human Genetics . 19 . 6 . 676–81 . June 2011 . 21368909 . 10.1038/ejhg.2011.1 . 3110050.
14. Web site: CTSZ interaction network . . 6 August 2016 .
15. Hafner A, Glavan G, Obermajer N, Živin M, Schliebs R, Kos J . Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X . Aging Cell . 12 . 4 . 604–14 . August 2013 . 23621429 . 10.1111/acel.12093 . 23835547 . free .