Biology Reference
In-Depth Information
leucine-rich repeat proteoglycans such as lumican, decorin, biglycan and fibro-
modulin that bind to collagen fibrils and limit their diameters may also limit the
accessibility of collagenases to cleave collagen fibrils.
5.9 Cathepsin K
Cathepsin K is a cysteine proteinase predominantly expressed in osteoclasts and to a
lesser extent in other cell types in soft tissues such as fibroblasts (see Chap. 3). A unique
property of the enzyme is its ability to cleave type I and II collagens in their helical
regions at an acidic pH (Kafienah et al.
1998
; Garnero et al.
1998a
). Collagenolytic
activity of cathepsin K is considered to be important in osteoclastic bone resorption, as
evidenced by the observation that deficiency in cathepsin K activity causes a rare bone
sclerosing disorder, pycnodysostosis (Gelb et al.
1996
), and that the disease-related
mutation in the cathepsin K gene leads to a loss of its collagenolytic activity (Hou et al.
1999
). Patients with pycnodysostosis typically have decreased bone resorption,
enhanced bone density and dwarfism (Fratzl-Zelman et al.
2004
). An osteopetrotic
phenotype was reported in cathepsin K-deficient mice (Saftig et al.
1998
). Studies of
Everts et al. (
2003
) have shown that cathepsin K is also important in lysosomal
degradation of phagocytosed collagens in soft connective tissue fibroblasts.
Biochemical studies of collagenolytic activity of cathepsin K have demonstrated
that the enzyme cleaves at multiple sites, primarily near the N-terminal side in triple
helical regions of interstitial collagens (Kafienah et al.
1998
; Garnero et al.
1998b
).
However, its collagenolytic activity is negligible without the presence of glycosa-
minoglycans (Li et al.
2000
). The most effective glycosaminoglycan is chondroitin
4-sulphate (C4-S) with which the enzyme forms a multimeric complex by associat-
ing with a C4-S chain (Li et al.
2002
). Li et al. (
2008
) have recently reported the 3D
structure of the complex formed between cathepsin K and C4-S, which revealed a
“beads-on-a-string”-like organization. The
K
d
value of their interaction is about
10 nM. Multiple cathepsin K molecules bound to a single C4-S chain forming a
cosine wave-like curve, where one cathepsin K molecule periodically binds at each
maximum and minimum of the cosine wave. One molecule of cathepsin K occupies
three disaccharide units of C4-S which is bound to the R-domain located on the
opposite side of the active site of the enzyme, keeping the enzyme's active site
unobstructed. In this area, several positively charged side chains interact directly
with the negatively charged groups of C4-S. Another important set of interactions
are located in a single turn of the helix, close to the N-terminus of the enzyme,
containing a basic amino acid triplet (Arg
8
-Lys
9
-Lys
10
) that forms multiple hydro-
gen bonds with the carboxylate or the four-sulphate groups of C4-S. It is speculated
that the collagen triple helix could be accommodated between two spatially adja-
cent cathepsin K molecules bound to C4-S and one active site of the two enzyme
molecules may be directed towards the scissile bond of the collagen. However,
cleavage of the triple helical collagen requires a partial unwinding of collagen
