Biology Reference
In-Depth Information
only partially active. For full activation, the Gly
78
-Phe
79
bond needs to be cleaved
by MMP-3 or MMP-10 (Kn
auper et al.
1996b
). Crystal structures of the fully
activated catalytic domain of MMP-8 showed that the ammonium group of Phe
79
forms a salt bridge with the carboxylate of Asp
232
(Reinemer et al.
1994
), but this
salt bridge fails to form in the partially activated forms. How this salt bridge affects
the collagenolytic activity is not understood. For pro-MMP-13, MMP-3, MMP-14
and plasmin can cleave the bait region, but in this case full activation of MMP-13 is
attained by autolysis by generating the enzyme with the N-terminal Tyr
85
(Knauper
et al.
1996a
,
c
).
An organomercurial compound (e.g., 4-aminophenyl mercuricacetate) is com-
monly used to activate a number of pro-MMPs including above collagenases.
Glutathione-dependent activation of pro-MMP-1, -8 and -9 is induced by peroxy-
nitrite (ONOO
), an oxidizing agent formed during inflammation (Okamoto et al.
2001
). These activation systems perturb the proenzyme structure possibly by
reacting with the cysteine residues in the cysteine switch. However, in the case of
MMP-1 and MMP-8, they are only partially activated due to autolysis.
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5.2.3 Activation of pro-MMP-2 by MMP-14 on the Cell Surface
MMP-2 cleaves a number of ECM macromolecules, but its activity on heat-
denatured collagens, gelatin, is most prominent. Because of this activity it is called
gelatinase A, MMP-9 being gelatinase B. In 1995, Aimes and Quigley reported that
MMP-2 cleaves type I collagen in a similar manner as MMP-1 (Aimes and Quigley
1995
). While the biological activator of pro-MMP-2 had long been an enigma, Sato
et al. (
1994
) cloned MMP-14 and shown it to be activator of pro-MMP-2. This
activation requires the formation of a tetramolecular complex of pro-MMP-2-
TIMP-2-(MMP-14)
2
. TIMP-2 is one of four paralogous tissue inhibitors of metallo-
proteinases (TIMPs), endogenous inhibitors of MMPs and pro-MMP-2 in the
medium can be bound to TIMP-2 through interaction between the Hpx domain
of pro-MMP-2 and the C-terminal domain of TIMP-2 (Fridman et al.
1992
;
Willenbrock et al.
1993
). Since this complex is capable of binding and inhibiting
active MMPs, it binds to the catalytic domain of MMP-14 on the plasma membrane,
which presumably presents the propeptide of pro-MMP-2 to an adjacent MMP-14
for hydrolysis of the Asn
37
-Leu
38
bond in the propeptide. Subsequently, it is fully
activated by autocleavage of the Asn
80
-Tyr
81
bond. Fully activated MMP-2, how-
ever, may be gradually inhibited by TIMP-2 present in the activated complex (Itoh
et al.
1998
). Thus, activated MMP-2 may participate in pericellular collagenolysis
for a limited period of time. MMP-14 itself has collagenolytic activity (Ohuchi et al.
1997
) and can also activate pro-MMP-13 (Kn
auper et al.
1996c
). Therefore,
MMP-14 appears to be one of the key enzymes controlling pericellular collageno-
lysis. This is evident from MMP-14-null mice, which exhibit impaired collageno-
lytic activity (Holmbeck et al.
1999
).
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