期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 383, 期 1, 页码 78-91出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.07.038
关键词
glycosaminoglycan; sulfhydryl peptidase; collagenase; conformation of Chondroitin Sulfate; binary complex with Cathepsin K
资金
- Alberta Synchrotron Institute
- Alberta Provincial Government (ASRA)
- Alberta Ingenuity Fund
- Government of Canada Western Economic Diversification
- National Institutes of Health [AR 48669]
- Canadian Institutes of Health Research [FRN 12831]
Cathepsin K is the major collagenolytic enzyme produced by bone-resorbing osteoclasts. We showed earlier that the unique triple-helical collagen-degrading activity of cathepsin K depends on the formation of complexes with bone-or cartilage-resident glycosaminoglycans, such as chondroitin 4-sulfate (C4-S). Here, we describe the crystal structure of a 1:n complex of cathepsin K:C4-S inhibited by E64 at a resolution of 1.8 angstrom. The overall structure reveals an unusual beads-on-a-string-like organization. Multiple cathepsin K molecules bind specifically to a single cosine curve-shaped strand of C4-S with each cathepsin K molecule interacting with three disaccharicle residues of C4-S. One of the more important sets of interactions comes from a single turn of helix close to the N terminus of the proteinase containing a basic amino acid triplet (Arg8-Lys9-Lys10) that forms multiple hydrogen bonds either to the caboxylate or to the 4-sulfate groups of C4-S. Altogether, the binding sites with C4-S are located in the R-domain of cathepsin K and are distant from its active site. This explains why the general proteolytic activity of cathepsin K is not affected by the binding of chondroitin sulfate. Biochemical analyses of cathepsin K and C4-S mixtures support the presence of a 1:n complex in solution; a dissociation constant, K-d, of about 10 nM was determined for the interaction between cathepsin K and C4-S. (C) 2008 Elsevier Ltd. All rights reserved.
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