Biology Reference
In-Depth Information
preferentially interacts with the
1(I) chain was cleaved more
readily under the above experimental conditions. The unwinding activity of
MMP-1(E200A) detected with neutrophil elastase as a cutter was blocked by an
active site-directed hydroxamate inhibitor of MMPs, suggesting that the active site
of the enzyme is necessary for the unwinding activity, presumably as one of
adaptors of the unwound
a
2(I) chain, as
a
a
2(I) chain.
5.5.2 The Stultz Model
The collagenase-induced collagen unwinding model proposed by (Chung et al.
2004
) was challenged by Stultz and colleagues (Nerenberg et al.
2008
). Based on
their theoretical molecular simulation, they propose that collagen triple helix
around the collagenase-cleavage site is less stable than the rest of the molecule
and tends to be partially unfolded. Such unfolded “vulnerable” state is considered to
be sufficient for collagenases to recognize and hydrolyzes the peptide bonds. Their
theoretical calculation of free energy of collagen-like triple helical peptide (THP)
containing the collagenase-cleavage site sequence of collagen III suggests that it
adopts both native and partially unfolded states (Stultz
2002
), and computational
simulations of the collagenase-cleavage site of collagen I suggest that the unfolding
of the
1(I) chains
(Nerenberg and Stultz
2008
). Higher mobility of polypeptide backbones around this
site has been predicted as it has less imino acids compared to the rest of the collagen
chain (Brown et al.
1977
; Fields
1991
). This notion is also supported by the study of
Fiori et al. (
2002
) with a synthetic heterotrimeric triple helical peptide of the
a
2(I) chain is energetically favoured relative to the unfolding of
a
a
1(I)
and
2(I) sequences around collagenase-cleavage site of collagen I. The structure of
fibrillar type I collagen of rat tail tendon determined at room temperature reported
by Orgel et al. (
2006
) also indicates that the triple helical structure around the
collagenase-susceptible region is relaxed compared to the rest of the triple helical
collagen. However, the alignment of the
a
2(I) chain of Orgel's model to the active
site of MMP-1 shows a number of serious molecular clashes, and for collagenases
to cleave the
a
a
a
1(I) chain considerable rearrangements of the
polypeptide chain fold need to take place (see below).
2(I) chain and
5.5.3 Further Insights into Triple Helicase Activity Provided
by the Catalytic Domains of Collagenase Mutants
If the vulnerable state were sufficient for collagenase to recognize and cleave triple
helical collagen, it should then be susceptible to the catalytic domains of MMP-1,
MMP-3 and possibly other non-collagenolytic proteinases, even though their acti-
vities on collagen may be considerably low. Furthermore, the ratio of collagenolytic
