Linked Life Data

12039963

Source:http://linkedlifedata.com/resource/pubmed/id/12039963

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
32
pubmed:dateCreated
2002-8-5
pubmed:abstractText
Bone resorption in balance with bone formation is vital for the maintenance of the skeleton and is mediated by osteoclasts. Cathepsin K is the predominant protease in osteoclasts that degrades the bulk of the major bone forming organic component, type I collagen. Although the potent collagenase activity of cathepsin K is well known, its mechanism of action remains elusive. Here, we report a cathepsin K-specific complex with chondroitin sulfate, which is essential for the collagenolytic activity of the enzyme. The complex is an oligomer consisting of five cathepsin K and five chondroitin sulfate molecules. Only the complex exhibits potent triple helical collagen-degrading activity, whereas monomeric cathepsin K has no collagenase activity. The primary substrate specificity of cathepsin K is not altered by complex formation, suggesting that the protease-chondroitin sulfate complex primarily facilitates the destabilization and/or the specific binding of the triple helical collagen structure. Inhibition of complex formation leads to the loss of collagenolytic activity but does not impair the proteolytic activity of cathepsin K toward noncollagenous substrates. The physiological relevance of cathepsin K complexes is supported by the findings that (i) the content of chondroitin sulfate present in bone and accessible to cathepsin K activity is sufficient for complex formation and (ii) Y212C, a cathepsin K mutant that causes pycnodysostosis (a bone sclerosing disorder) and that has no collagenase activity but remains potent as a gelatinase, is unable to form complexes. These findings reveal a novel mechanism of bone collagen degradation and suggest that targeting cathepsin K complex formation would be an effective and specific treatment for diseases with excessive bone resorption such as osteoporosis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
28669-76
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12039963-Bone and Bones, pubmed-meshheading:12039963-Cathepsin K, pubmed-meshheading:12039963-Cathepsins, pubmed-meshheading:12039963-Chondroitin Sulfates, pubmed-meshheading:12039963-Collagen, pubmed-meshheading:12039963-Collagenases, pubmed-meshheading:12039963-Dose-Response Relationship, Drug, pubmed-meshheading:12039963-Humans, pubmed-meshheading:12039963-Hydrogen-Ion Concentration, pubmed-meshheading:12039963-Kinetics, pubmed-meshheading:12039963-Light, pubmed-meshheading:12039963-Mutation, pubmed-meshheading:12039963-Peptides, pubmed-meshheading:12039963-Protein Binding, pubmed-meshheading:12039963-Scattering, Radiation, pubmed-meshheading:12039963-Sclerosis, pubmed-meshheading:12039963-Substrate Specificity, pubmed-meshheading:12039963-Temperature, pubmed-meshheading:12039963-Ultracentrifugation
pubmed:year
2002
pubmed:articleTitle
Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate.
pubmed:affiliation
Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York 10029, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.