Cathepsin k

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<scene name='72/727885/Cathepsin_k_helix_sheet/1'>Cathepsin K</scene> 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 <ref name="mcq">doi:10.1074/jbc.272.21.13955</ref><ref name="boss">doi:10.1074/jbc.271.21.12517</ref>. 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 <ref name="uniprot">http://www.uniprot.org/uniprot/P43235#structure</ref><ref name="protparam">"CATK_HUMAN (P43235)." http://web.expasy.org/protparam</ref>. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa <ref name="mcq"/><ref name="boss"/>. Cathepsin K is active in acidic conditions, within a pH range of 4-6 <ref name="garn"/>.
<scene name='72/727885/Cathepsin_k_helix_sheet/1'>Cathepsin K</scene> 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 <ref name="mcq">doi:10.1074/jbc.272.21.13955</ref><ref name="boss">doi:10.1074/jbc.271.21.12517</ref>. 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 <ref name="uniprot">http://www.uniprot.org/uniprot/P43235#structure</ref><ref name="protparam">"CATK_HUMAN (P43235)." http://web.expasy.org/protparam</ref>. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa <ref name="mcq"/><ref name="boss"/>. Cathepsin K is active in acidic conditions, within a pH range of 4-6 <ref name="garn"/>.
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The signal peptide sequence consists of hydrophobic amino acids, with the exception of one serine residue <ref name="protparam"/>. 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%) <ref name="protparam"/>. 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 <ref name="protparam"/>.
The <scene name='72/727885/Cathepsin_k_active_site/1'>active site</scene> of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 <ref name="zao">doi:10.1038/nsb0297-109</ref>.The cleft containing the active site is flanked by two <scene name='72/727885/Cathepsin_k_globules/1'>globular domains</scene> <ref name="zao"/><ref name="lut">DOI:doi:10.1096/fj.06-7924com</ref>. Protease activity is induced by the entrance of the substrate into the active site cleft <ref name="lut"/>.
The <scene name='72/727885/Cathepsin_k_active_site/1'>active site</scene> of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 <ref name="zao">doi:10.1038/nsb0297-109</ref>.The cleft containing the active site is flanked by two <scene name='72/727885/Cathepsin_k_globules/1'>globular domains</scene> <ref name="zao"/><ref name="lut">DOI:doi:10.1096/fj.06-7924com</ref>. Protease activity is induced by the entrance of the substrate into the active site cleft <ref name="lut"/>.
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== Disease ==
== Disease ==
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Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, caused by reduced bone resorption and characterized by increased bone density and short stature <ref name="gelb">DOI: 10.1126/science.273.5279.1236</ref>. HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis <ref name="gelb"/><ref name="asa">DOI: 10.1126/science.1150110</ref>.
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Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, caused by reduced bone resorption and characterized by increased bone density and short stature <ref name="gelb">DOI: 10.1126/science.273.5279.1236</ref>. HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis <ref name="gelb"/><ref name="hou"/>.
Cathepsin K may also take part in atherosclerosis, as high activity of cathepsin K has beed discovered in atherosclerotic lesions <ref name="lut"/>. Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins <ref name="lind"/>. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions <ref name="lind"/>. Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 <ref name="lind"/>. Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity <ref name="lut"/><ref name="lind"/>.
Cathepsin K may also take part in atherosclerosis, as high activity of cathepsin K has beed discovered in atherosclerotic lesions <ref name="lut"/>. Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins <ref name="lind"/>. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions <ref name="lind"/>. Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 <ref name="lind"/>. Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity <ref name="lut"/><ref name="lind"/>.

Revision as of 23:18, 13 April 2016

Human Cathepsin K

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Contents

Introduction

Cathepsin K is a member of a large family of lysosomal cysteine proteases, which have been under extensive study over the past decade [1][2][3]. Cathepsin enzymes were originally considered general proteases found in the lysosomes of all cell types; however, recent studies have found the expression of certain cathepsins - including cathepsin K - in specific tissue cells [3].

Cathepsin K is the most abundant cysteine protease produced by osteoclasts, the multinuclear cells responsible for bone resorption [4][5]. This enzyme is also expressed in chondrocytes and is capable of the cleavage of type II collagen, the component of cartilage which provides tensile strength [1]. Cathepsin K is has also been found in macrophages and appear capable of the degradation of both apolipoproteins and elastin [3].

Structure

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 [6][7]. 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 [8][9]. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa [6][7]. Cathepsin K is active in acidic conditions, within a pH range of 4-6 [10].

The signal peptide sequence consists of hydrophobic amino acids, with the exception of one serine residue [9]. 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%) [9]. 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 [9].

The of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 [11].The cleft containing the active site is flanked by two [11][2]. Protease activity is induced by the entrance of the substrate into the active site cleft [2].


Function

Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage matrices [12][1]. This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix [10][3]. 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 [3].

Cathepsin K is also capable of degrading apolipoproteins, which reside in macrophages and facilitate the efflux of cholesterol from these cells [13]. The degradation of apolipoproteins has shown to increase the cholesterol content in macrophages [13].

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 [14]. HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis [14][12].

Cathepsin K may also take part in atherosclerosis, as high activity of cathepsin K has beed discovered in atherosclerotic lesions [2]. Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins [13]. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions [13]. Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 [13]. Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity [2][13].

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 [4]. However, it has been suggested that the inhibition of Cathespin K may not result in strengthened bone tissue [5]. Osteoclasts implement bone resorption in two sequential processes. First, acid is secreted onto the bone surface to demineralize the bone tissue [11][4]. Second, the acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix [11][4]. 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 [5][11][4].

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 [12]. 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 [12].

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 [13].

References

  1. ↑ 1.0 1.1 1.2 doi: https://dx.doi.org/10.1042/bj3310727
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Arav VI, Slesarev SM, Slesareva EV. A method for extirpation of the pineal gland in albino rats. Bull Exp Biol Med. 2008 Sep;146(3):382-4. PMID:19240866 doi:doi
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta. 2012 Jan;1824(1):68-88. doi: 10.1016/j.bbapap.2011.10.002. , Epub 2011 Oct 12. PMID:22024571 doi:http://dx.doi.org/10.1016/j.bbapap.2011.10.002
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008 Jan;83(1):172-6. Epub 2007 Dec 12. PMID:18073778 doi:http://dx.doi.org/10.1038/sj.clpt.6100450
  5. ↑ 5.0 5.1 5.2 Vaananen K. Mechanism of osteoclast mediated bone resorption--rationale for the design of new therapeutics. Adv Drug Deliv Rev. 2005 May 25;57(7):959-71. Epub 2005 Apr 15. PMID:15876398 doi:http://dx.doi.org/10.1016/j.addr.2004.12.018
  6. ↑ 6.0 6.1 doi: https://dx.doi.org/10.1074/jbc.272.21.13955
  7. ↑ 7.0 7.1 doi: https://dx.doi.org/10.1074/jbc.271.21.12517
  8. ↑ http://www.uniprot.org/uniprot/P43235#structure
  9. ↑ 9.0 9.1 9.2 9.3 "CATK_HUMAN (P43235)." http://web.expasy.org/protparam
  10. ↑ 10.0 10.1 doi: https://dx.doi.org/10.1074/jbc.273.48.32347
  11. ↑ 11.0 11.1 11.2 11.3 11.4 doi: https://dx.doi.org/10.1038/nsb0297-109
  12. ↑ 12.0 12.1 12.2 12.3 Hou WS, Li Z, Gordon RE, Chan K, Klein MJ, Levy R, Keysser M, Keyszer G, Bromme D. Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol. 2001 Dec;159(6):2167-77. PMID:11733367 doi:http://dx.doi.org/10.1016/S0002-9440(10)63068-4
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 doi: https://dx.doi.org/10.1016/j.bbrc.2003.11.020
  14. ↑ 14.0 14.1 doi: https://dx.doi.org/10.1126/science.273.5279.1236

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