Cathepsin G

Structure

Gene

The CTSG gene is located at chromosome 14q11.2, consisting of 5 exons. Each residue of the catalytic triad is located on a separate exon. Five polymorphisms have been identified by scanning the entire coding region. Cathepsin G homologs evolved from a common ancestor via gene duplication.

Protein

Cathepsin G is a 255-amino-acid-residue protein including an 18-residue signal peptide, a two-residue activation peptide at the N-terminus and a carboxy terminal extension. The activity of cathepsin G depends on a catalytic triad composed of aspartate, histidine and serine residues which are widely separated in the primary sequence but close to each other at the active site of the enzyme in the tertiary structure.

Function

Cathepsin G has a specificity similar to that of chymotrypsin C, but it is most closely related to other immune serine proteases, such as neutrophil elastase and the granzymes. As a neutrophil serine protease, was first identified as degradative enzyme that acts intracellularly to degrade ingested host pathogens and extracellularly in the breakdown of ECM components at inflammatory sites. It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases. Transcript variants utilizing alternative polyadenylation signals exist for this gene. Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above. Other functions of cathepsin G have been reported, including cleavage of receptors, conversion of angiotensin I to angiotensin II, platelet activation, and induction of airway submucosal gland secretion. Potential implications of the enzyme in blood-brain barrier breakdown was also found.

Clinical significance

Cathepsin G has been reported to play an important role in a variety of diseases, including rheumatoid arthritis, coronary artery disease, periodontitis, ischemic reperfusion injury, and bone metastasis. It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis. A recent study shows that patients with CTSG gene polymorphisms have higher risk of chronic postsurgical pain, suggesting cathepsin G may serve as a novel target for pain control and a potential marker to predict chronic postsurgical pain. An upregulation of cathepsin G was reported in studies of keratoconus.

Interactions

Cathepsin G has been found to interact with:

• SERPINB1 Cathepsin G is inhibited by:
• [2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA)
• Caesalpinia echinata elastase inhibitor
• N-Arylacyl O-sulfonated aminoglycosides Cathepsin G lowers levels of:
• Low-density lipoprotein

References

References

1. (November 1968). "Mediators of inflammation in leukocyte lysosomes. IX. Elastinolytic activity in granules of human polymorphonuclear leukocytes". The Journal of Experimental Medicine.
2. (December 1988). "Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters". The Journal of Clinical Investigation.
3. (1979). "Ciba Foundation Symposium 75 - Protein Degradation in Health and Disease".
4. (October 1984). "Similarities between human and rat leukocyte elastase and cathepsin G". European Journal of Biochemistry.
5. (September 2001). "Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases". Arteriosclerosis, Thrombosis, and Vascular Biology.
6. (1991). "Zymogen activation specificity and genomic structures of human neutrophil elastase and cathepsin G reveal a new branch of the chymotrypsinogen superfamily of serine proteinases". Biomedica Biochimica Acta.
7. (April 1987). "Molecular cloning of human cathepsin G: structural similarity to mast cell and cytotoxic T lymphocyte proteinases". Biochemistry.
8. (February 2008). "Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions". Biochimie.
9. (June 2014). "Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins". Journal of Immunology.
10. (July 2006). "Neutrophil serine proteases: specific regulators of inflammation". Nature Reviews. Immunology.
11. "Entrez Gene: CTSG cathepsin G".
12. (January 1991). "Human lysosomal cathepsin G and granzyme B share a functionally conserved broad spectrum antibacterial peptide". The Journal of Biological Chemistry.
13. (January 2004). "Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G". Journal of Immunology.
14. (February 2001). "More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control". Journal of Leukocyte Biology.
15. (August 1982). "Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases". The Journal of Biological Chemistry.
16. (March 2000). "Cathepsin G activates protease-activated receptor-4 in human platelets". The Journal of Biological Chemistry.
17. (September 1991). "Role of mast cell and neutrophil proteases in airway secretion". The American Review of Respiratory Disease.
18. (September 1997). "Neutral proteases and disruption of the blood-brain barrier in rat". Brain Research.
19. (May 2007). "Macrophages and their products in rheumatoid arthritis". Current Opinion in Rheumatology.
20. (Jan–Feb 2007). "Fabrication of artificial endothelialized tubes with predetermined three-dimensional configuration from flexible cell-enclosing alginate fibers". Biotechnology Progress.
21. (January 2016). "Neutrophil serine proteases and their endogenous inhibitors in coronary artery ectasia patients". [[Anatolian Journal of Cardiology]].
22. (March 2007). "Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients". Molecular Immunology.
23. (March 2007). "Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys". The American Journal of Pathology.
24. (September 2002). "The role of neutrophil elastase in acute lung injury". European Journal of Pharmacology.
25. (April 2003). "Proteases and lung injury". Critical Care Medicine.
26. (2015). "The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung". Mediators of Inflammation.
27. (October 2015). "Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain: An Experimental and Clinical Genetic Study". Anesthesiology.
28. (February 1997). "Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas". Investigative Ophthalmology & Visual Science.
29. (May 2013). "SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G". Blood.
30. (2012). "Cathepsin G inhibitor prevents ultraviolet B-induced photoaging in hairless mice via inhibition of fibronectin fragmentation". Dermatology.
31. (December 2013). "Using a Caesalpinia echinata Lam. protease inhibitor as a tool for studying the roles of neutrophil elastase, cathepsin G and proteinase 3 in pulmonary edema". Phytochemistry.
32. (February 2016). "N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3". Glycobiology.
33. (November 2014). "Cathepsin G activity lowers plasma LDL and reduces atherosclerosis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.