Biology Reference
In-Depth Information
2.4 Cathepsins and Collagen Degradation
Triple helical type I and II collagens are highly resistant to proteolysis. Few
collagenases such as the matrix metalloproteases MMP1, MMP8, and MMP13
and the cysteine protease, cathepsin K, are able to hydrolyze peptide bonds in the
triple helical domain of these collagens. MMPs employ a specific structural ele-
ment, called the hemopexin domain, to partially unfold the triple helix and cleave at
a single site (Chung et al.
2004
,
2000
). This mechanism is discussed in more detail
in Chap. 5. Cathepsins do not possess such a specific “unwinding” domain and most
of them are only capable of cleaving in the nonhelical telopeptide regions of
collagens (Etherington
1972
; Etherington and Evans
1977
). The only exception is
cathepsin K. Cathepsin K cleaves peptide bonds at multiple sites within the triple
helical domain (Garnero et al.
1998
; Kafienah et al.
1998
). This unique specificity is
facilitated by the formation of an oligomeric complex between cathepsin K mole-
cules and extracellular matrix-resident glycosaminoglycans (Li et al.
2000
). Molec-
ular weights of the complex are between 200 and 300 kDa, depending on the size of
the participating glycosaminoglycans (Li et al.
2002
). A recently solved structure of
a chondroitin sulfate/cathepsin K complex revealed the formation of a “beads on a
string”-like conformation (Li et al.
2008
) (Fig.
2.3a
). Critical interactions between
cathepsin K and chondroitin sulfate molecules exploit a positively charged patch of
lysine and arginine (R
8
K
9
K
10
;K
191
) residues close to the N- and C-termini of the
cathepsin K amino acid sequence. This glycosaminoglycan-binding site is distant
from the active site of the protease. Indeed, the binding between cathepsin K and
chondroitin sulfate occurs on the “back side” of the protease, which may explain
why complex formation with glycosaminoglycans does not interfere with the
efficacy and specificity of cathepsin K regarding noncollagen substrates (Li et al.
2008
). There is no significant difference between the kinetic parameters for the
cleavage of synthetic peptide substrates and the efficacy to cleave gelatin between
the monomeric and complex form of cathepsin K (Li et al.
2000
,
2002
). However,
in the absence of the complex, monomeric cathepsin K, like other cathepsins,
exhibits only the telopeptide cleavage capability and lacks its collagenase activity
(Li et al.
2002
). It is assumed that the complex functions to unfold triple helical
collagen, as does the hemopexin domain in MMPs. The exact mechanism of
unfolding is presently being investigated.
The collagenase activity of glycosaminoglycan/cathepsin K complexes appears
to depend on the nature and concentration of participating glycosaminoglycans. At
fixed weight per volume concentrations, certain glycosaminoglycans such as chon-
droitin and keratan sulfates promote the collagenase activity of cathepsin K,
whereas dermatan and heparan sulfates inhibit the collagenase activity (Li et al.
2004
). This may imply different binding modes for different glycosaminoglycans.
Moreover, a significant molar excess of any glycosaminoglycans over cathepsin K
inhibits the collagenase activity as well. This may have important implications for
the regulation of cathepsin K activity and may explain certain bone phenotypes
in diseases where the accumulation of glycosaminoglycans is causative as in
