Cathepsin k

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==Structure==
==Structure==
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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"/>.
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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"/>.
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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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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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Unlike other cathepsin enzymes, cathepsin k is active in acidic conditions, within a pH range of 4-6 <ref name="garn"/>.
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Unlike other cathepsin enzymes, cathepsin K is active in acidic conditions, within a pH range of 4-6 <ref name="garn"/>.
== Function ==
== Function ==

Revision as of 15:49, 6 April 2016

Human Cathepsin K

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Contents

Introduction

Cathepsin K is the most abundant cysteine protease produced by osteoclasts, the multinuclear cells responsible for bone resorption [1][2]. Osteoclasts implement bone resorption in two sequential processes. First, acid is secreted onto the bone surface to demineralize the bone tissue [3][1]. Second, the acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix [3][1].

Cathepsin K is also found in magrophages, cells involved in the storage of cholesterol [4].

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 [5][6]. 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 [7][8]. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa [5][6].

The of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 [3].The cleft containing the active site is flanked by two [3][9]. Protease activity is induced by the entrance of the substrate into the active site cleft [9].

Unlike other cathepsin enzymes, cathepsin K is active in acidic conditions, within a pH range of 4-6 [10].

Function

Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage matrices [11][12]. This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix [10].

Cathepsin K is also capable of degrading apolipoproteins, which reside in macrophages and facilitate the efflux of cholesterol from these cells [4].

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 [13]. Cathepsin K inhibitors have been thus thought potential treatments for diseases involving excessive bone or cartilage resorption, such as osteoporosis and autoimmue arthritis [1][11][14]. 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 [2].

Cathepsin K may also take part in atherosclerosis. Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins [4]. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic plaque [4]. High activity of cathepsin K has beed discovered in atherosclerotic lesions [9].

Relevance

</StructureSection>

References

  1. ↑ 1.0 1.1 1.2 1.3 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
  2. ↑ 2.0 2.1 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
  3. ↑ 3.0 3.1 3.2 3.3 doi: https://dx.doi.org/10.1038/nsb0297-109
  4. ↑ 4.0 4.1 4.2 4.3 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
  5. ↑ 5.0 5.1 doi: https://dx.doi.org/10.1074/jbc.272.21.13955
  6. ↑ 6.0 6.1 doi: https://dx.doi.org/10.1074/jbc.271.21.12517
  7. ↑ http://www.uniprot.org/uniprot/P43235#structure
  8. ↑ "CATK_HUMAN (P43235)." http://web.expasy.org/protparam
  9. ↑ 9.0 9.1 9.2 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
  10. ↑ 10.0 10.1 doi: https://dx.doi.org/10.1074/jbc.273.48.32347
  11. ↑ 11.0 11.1 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
  12. ↑ doi: https://dx.doi.org/10.1042/bj3310727
  13. ↑ doi: https://dx.doi.org/10.1126/science.273.5279.1236
  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

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