Cathepsin k

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The <scene name='72/727885/Cathepsin_k_active_site/4'>active site</scene> of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 <ref name="zao">PMID:9033588</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/4'>active site</scene> of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 <ref name="zao">PMID:9033588</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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<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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<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">PMID: 9153258</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"/>.
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 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"/>.

Revision as of 21:50, 22 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 that provides tensile strength [1]. Cathepsin K is has also been found in macrophages and appears capable of the degradation of both apolipoproteins and elastin [3].

Structure

The of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 [6].The cleft containing the active site is flanked by two [6][2]. Protease activity is induced by the entrance of the substrate into the active site cleft [2].

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 [7][8]. 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 [9][10]. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa [7][8]. Cathepsin K is active in acidic conditions, within a pH range of 4-6 [11].

The signal peptide sequence consists of hydrophobic amino acids, with the exception of one serine residue [10]. 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%) [10]. 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 [10].

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 [12][1][13]. This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix [11][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 seems to contribute to the inflammatory response [14][12]. Cathepsin K is expressed by inflammatory cells in response to detected pathogens, possibly in order to cleave pathogenic proteins [13].

Cathepsin K is also capable of degrading apolipoproteins, which reside in macrophages and facilitate the efflux of cholesterol from these cells [15]. The degradation of apolipoproteins has shown to increase the cholesterol content in macrophages [15].

Disease

Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, characterized by reduced bone resorption, increased bone density, and short stature [16]. HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis [16][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 [15]. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions [15]. Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 [15]. Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity [2][15].

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 [6][4]. Second, the acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix [6][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][6][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 [15].

References

  1. ↑ 1.0 1.1 1.2 Kafienah W, Bromme D, Buttle DJ, Croucher LJ, Hollander AP. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J. 1998 May 1;331 ( Pt 3):727-32. PMID:9560298
  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 6.2 6.3 6.4 Zhao B, Janson CA, Amegadzie BY, D'Alessio K, Griffin C, Hanning CR, Jones C, Kurdyla J, McQueney M, Qiu X, Smith WW, Abdel-Meguid SS. Crystal structure of human osteoclast cathepsin K complex with E-64. Nat Struct Biol. 1997 Feb;4(2):109-11. PMID:9033588
  7. ↑ 7.0 7.1 McQueney MS, Amegadzie BY, D'Alessio K, Hanning CR, McLaughlin MM, McNulty D, Carr SA, Ijames C, Kurdyla J, Jones CS. Autocatalytic activation of human cathepsin K. J Biol Chem. 1997 May 23;272(21):13955-60. PMID:9153258
  8. ↑ 8.0 8.1 doi: https://dx.doi.org/10.1074/jbc.271.21.12517
  9. ↑ http://www.uniprot.org/uniprot/P43235#structure
  10. ↑ 10.0 10.1 10.2 10.3 "CATK_HUMAN (P43235)." http://web.expasy.org/protparam
  11. ↑ 11.0 11.1 doi: https://dx.doi.org/10.1074/jbc.273.48.32347
  12. ↑ 12.0 12.1 12.2 12.3 12.4 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 Diaz A, Willis AC, Sim RB. Expression of the proteinase specialized in bone resorption, cathepsin K, in granulomatous inflammation. Mol Med. 2000 Aug;6(8):648-59. PMID:11055584
  14. ↑ Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, Nishikawa K, Latz E, Golenbock DT, Aoki K, Ohya K, Imai Y, Morishita Y, Miyazono K, Kato S, Saftig P, Takayanagi H. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science. 2008 Feb 1;319(5863):624-7. doi: 10.1126/science.1150110. PMID:18239127 doi:http://dx.doi.org/10.1126/science.1150110
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 doi: https://dx.doi.org/10.1016/j.bbrc.2003.11.020
  16. ↑ 16.0 16.1 doi: https://dx.doi.org/10.1126/science.273.5279.1236

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