Biology Reference
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Fig. 6.1 Distribution of positive charge on MMP-7 where sulfated GAGs could bind on (a) the
catalytic domain (Yu and Woessner
2000
) and (b) the zymogen with prodomain. Lysine are
arginine side chains are colored blue. The label “h” refers to
-strand. The back
of the catalytic domain lies in the foreground of panel (a) where the swath wraps around it. The
active site in the background has zinc ions (
gray
) and calcium ions (
brown
) around it. Panel (b)
adds the prodomain and its positive charges (upper right) that may account for the higher affinity of
the zymogen for heparin and C-4,6-S. The structure of pro-MMP-7 was predicted by homology
modeling, using the SWISS-MODEL server (Schwede et al.
2003
), using coordinates of the pro-
plus catalytic domains of MMP-3 (PDB accession code 1SLM) as the structural template. The
color code ranges from red at the N-terminus (top) of the prodomain to blue at the C-terminus
(bottom) of the catalytic domain. The active site is in the center with its helix (
light blue
) just to the
left of it
-helix and “s” to
a
b
the prodomain. In the structure predicted for pro-MMP-7, the nine positive charges
are distributed all over the prodomain (Fig.
6.1b
). Seven of these arginines and
lysines are found in the three amphipathic helices of the prodomain. Multiple
orientations of binding of sulfated GAGs to the prodomain are conceivable. GAG
chains can be more confidently envisioned to follow the arc of positive charge
around the back of the catalytic domain (Fig.
6.1
).
Two potential mechanisms of activation are possible. One would be an alloste-
ricmeansofactivationakintotheallosteric effects of association of either gelatin
or tissue kallikrein with pro-MMP-9 that disrupt cysteine coordination of the
zinc (Bannikov et al.
2002
; Rosenblum et al.
2007
), as described in Sect.
6.1.1
.
An important alternative mechanism would be the concentrating effects of colo-
calizing pro-MMPs on a GAG chain like the “beads-on-a-string” association of
cathepsin K with chondroitin-4-sulfate, observed to bind surfaces of cathepsin K
distant from its active site (Li et al.
2008a
,
b
). The multiple sites of potential GAG
contact with the prodomain suggest that effects of this might allosterically affect
the cysteine thiolate coordination of the zinc at the procatalytic interface. GAG
chains might also be able to bridge from prodomain to the cradle behind the
catalytic domain in the activation process. The associations of GAGs with pro-
MMP-7 might also serve to draw togetherothermoleculesofMMP-7,perhaps
as beads on GAG string(s), to provide a concentrating effect that would pro-
mote bimolecular proteolytic activation. Thus, how GAGs promote activation of
pro-MMP-7 remains an open question.
