Cathepsin k

spinqualitylabelsall models Human Cathepsin K Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Introduction Cathepsin K is a member of a large family of lysosomal cysteine proteases, which have been under extensive study over the past decade . Cathepsin enzymes were originally considered general proteases found in the lysosomes of all cell types. However, recent studies have found the expression of Cathepsin K in specific tissue cells . Cathepsin K is the most abundant cysteine protease produced by osteoclasts, the multinuclear cells responsible for bone resorption . This enzyme is also specifically expressed in chondrocytes and is capable of the cleavage of type II collagen, the component of cartilage that provides tensile strength . Cathepsin K is has additionally been identified in macrophages and tumor cells and appears capable of the degradation of both apolipoproteins and elastin . Structure The active site of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 .The cleft containing the active site is flanked by two globular domains . Protease activity is induced by the entrance of the substrate into the active site cleft . Cathepsin K is called a cysteine protease because the cysteine residue functions as the nucleophile . The cysteine residue becomes deprotonated, yielding a negavitely charged thiolate anion, which attacks the substrate peptide bond . Proper function of CYS25 requires the formation of an ion pair with the neighboring basic histidine residue . Cathepsin K is initially synthesized in its inactive form, pre-procathepsin k, a 37-kDa protein made up of a single peptide chain 329 amino acids in length . The pre-procathepsin k sequence has three distinct features: a signal peptide, consisting of the first 15 amino acids at the N-terminus; a propeptide, comprising amino acids 16-114; and the main chain, which makes up the final 215 amino acids ending at the C-Terminus . When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa . Cathepsin K is active in acidic conditions, within a pH range of 4-6 . The signal peptide sequence consists of hydrophobic amino acids, with the exception of one serine residue . The propeptide feature contains residues of all 20 standard amino acids, excluding only cysteine and phenylalanine, with the majority comprising leucine (12.1%) and glutamate (11.1%) . The activated enzyme, lacking the signal peptide and propeptide sequences, is approximately 54% hydrophillic and 46% hydrophobic, containing 19 negatively charged residues and 26 positively charged residues . This net positive charge may contribute to the stability of cathepsin K at low pH . Function Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage matrices, and are highly expressed in osteoclasts and chondroclasts . This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix . With facilitation by the protein chondroitin sulfate, cathepsin K forms a complex with other cathepsin K proteins to unravel and cleave the collagen triple helix . Cathepsin K is also capable of degrading apolipoproteins, which reside in macrophages and facilitate the efflux of cholesterol from these cells . The degradation of apolipoproteins has shown to increase the cholesterol content in macrophages, which is an initial step in arterial plaque formation . Cathepsin K seems to contribute to the inflammatory response . Cathepsin K is expressed by inflammatory cells in response to detected pathogens, possibly in order to cleave pathogenic proteins . Disease Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, characterized by reduced bone resorption, increased bone density, and short stature . HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis . Cathepsin K may also take part in atherosclerosis, as high activity of cathepsin K has beed discovered in atherosclerotic lesions . Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins . As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions . Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 . Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity . High expression of cathepsin K has been discovered in breast tumor cells, including those metastasized to bone tissue . As cathepsin K is capable of extracellular collagen degradation, this protease may function in tumor cells as a means of bone tissue invasion . Relevance Cathepsin K inhibitors have been thought potential treatments for osteoporosis, as high collagenolytic activity by cathepsin K has been identified among patients with this condition . However, it has been suggested that the inhibition of Cathespin K may not result in strengthened bone tissue . Osteoclasts implement bone resorption in two sequential processes. First, acid is secreted onto the bone surface to demineralize the bone tissue . Second, the acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix . Since demineralization of bone is induced by acid secretion and can continue without cathepsin K, the inhibition of this protease may merely result in the accumulation of weakened bone tissue . As cathepsin K takes part in cartilage degradation by cleavage of type II collagen, the inhibition of this protease could be a treatment for rheumatoid arthritis . Articular bone and cartilage degradation, as seen in rheumatoid arthritis, is largely conducted by osteoclasts and synovial fibroblasts, which highly express cathepsin K in inflamed arthritic joint tissue . Cathepsin K inhibitors have also been considered for the treatment or prevention of atherosclerosis, as cathepsin K promotes the accumulation of cholesterol in macrophages, leading to foam cell production and atherosclerotic lesions . Expression of cathepsin K has been identified in breast cancer tumor cells, as well as metastases embedded in bone tissue . Since bone is a common site for tumor metastasis, the inhibition of cathepsin K in tumor cells may prevent or impede the development of malignant bone tumors .

Content Donors

Hamed Aldhahri, Casey Bartel, Stuart Harris, Luke Parry, Lauren Sharpe, and Allison Weinschreider contributed to the research of cathepsin K presented in the article.

Proteopedia Page Contributors and Editors (what is this?)

Lauren Sharpe, Alexander Berchansky, Michal Harel