Cathepsin k

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 8: Line 8:
<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"/>.
<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"/>.
-
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 <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 large globular domains <ref name="zao"/><ref name="lut">doi:10.1096/fj.06-7924com</ref>.

Revision as of 12:25, 6 April 2016

Human Cathepsin K

Drag the structure with the mouse to rotate

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]. The acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix [3][1].

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 [4][5]. 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 [6][7]. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature Cathepsin K protein weighing 27-kDa [4][5].

The of Cathepsin K consists of three residues: CYS25, HIS162, and ASN182 [3]. The cleft containing the active site is flanked by two large globular domains [3][8].


Function

Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage matrices [9][10]. This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix [11].

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 [12]. Cathepsin K inhibitors have been thus thought potential treatments for diseases involving excessive bone or cartilage resorption, such as osteoporosis and autoimmue arthritis [1][9][13]. 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].

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 doi: https://dx.doi.org/10.1074/jbc.272.21.13955
  5. ↑ 5.0 5.1 doi: https://dx.doi.org/10.1074/jbc.271.21.12517
  6. ↑ http://www.uniprot.org/uniprot/P43235#structure
  7. ↑ "CATK_HUMAN (P43235)." http://web.expasy.org/protparam
  8. ↑ doi: https://dx.doi.org/10.1096/fj.06-7924com
  9. ↑ 9.0 9.1 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
  10. ↑ doi: https://dx.doi.org/10.1042/bj3310727
  11. ↑ doi: https://dx.doi.org/10.1074/jbc.273.48.32347
  12. ↑ doi: https://dx.doi.org/10.1126/science.273.5279.1236
  13. ↑ 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

Proteopedia Page Contributors and Editors (what is this?)

Lauren Sharpe, Michal Harel, Alexander Berchansky

Retrieved from "http://52.214.119.220/wiki/index.php/Cathepsin_k"
Personal tools