Cathepsin k
From Proteopedia
Contents |
Structure
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The of Cathepsin K consists of three residues: cysteine 25, histidine 162, and asparagine 182 (8).
Function
Cathepsin K is the most abundant cysteine protease produced by osteoclasts, the multinuclear cells responsible for bone resorption (6,7). Osteoclasts implement bone resorption by secreting acid onto the bone surface which demineralizes bone tissue, followed by proteases – including cathepsins – which degrade the bone matrix (6,8). Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage (4,5). This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix (2).
Disease
Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, caused by reduced bone resorption and characterized by increased bone density and short stature (3). Cathepsin K inhibitors have been thus thought potential treatments for diseases involving excessive bone or cartilage resorption, such as osteoporosis and autoimmue arthritis (1,4,6). However, as demineralization of bone can continue without Cathepsin k, the inhibition of Cathespin K may merely result in the accumulation of weakened bone tissue (7).
Relevance
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References
1. Asagiri, M., Hirai, T., Kunigami, T., et.al. (2008). Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science, 319(5863), 624-627.
2. Garnero, P., Borel, O., Byrjalsen, I., et.al. (1998). The collagenolytic activity of cathepsin K is unique among mammalian proteinases. Journal of Biological Chemistry,273(48), 32347-32352.
3. Gelb, B. D., Shi, G. P., Chapman, H. A., & Desnick, R. J. (1996). Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency.Science, 273(5279), 1236-1238.
4. Hou, W. S., Li, Z., Gordon, R. E., et.al. (2001). Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. The American journal of pathology, 159(6), 2167-2177.
5. Kafienah, W. E., Bromme, D., Buttle, D. J., et.al. (1998). Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochemical Journal,331(3), 727-732.
6. Stoch, S. A., & Wagner, J. A. (2008). Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clinical Pharmacology & Therapeutics, 83(1), 172-176.
7. Väänänen, K. (2005). Mechanism of osteoclast mediated bone resorption—rationale for the design of new therapeutics. Advanced drug delivery reviews,57(7), 959-971.
8. Zhao, B., Janson, C. A., Amegadzie, B. Y., et.al. (1997). Crystal structure of human osteoclast cathepsin K complex with E-64. Nature Structural & Molecular Biology, 4(2), 109-111.
