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In-Depth Information
catalytic domain. The metzincin subfamily of metalloproteases is characterized by
a 3-histidine zinc-binding motif and a conserved methionine turn following the
active site (Bode et al.
1993
) and includes the reprolysins or ADAMs (A Disintegrin
And Metalloproteinases), serralysins, astacins, and matrixins (aka: matrix metallo-
proteinases; MMPs) (St
ocker et al.
1995
). In this chapter, we focus on MMPs, their
roles in turnover, remodeling, and degradation of extracellular matrix (ECM)
proteins, and how their catalytic activity is governed by the action of the tissue
inhibitors of metalloproteinases (TIMPs).
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1.1.2 The Defining Features of MMPs
MMPs comprise a family of 25 related, yet distinct gene products, of which 24 are
found in mammals (Table
1.1
). The structural features of MMPs have been thor-
oughly discussed in several reviews (Maskos and Bode
2003
; Massova et al.
1998
;
Nagase et al.
2006
; Page-McCaw et al.
2007
), which have all highlighted the pre-
sence of two conserved motifs, the pro- and catalytic domains, that are common to
all but one member (Fig.
1.1
). The prodomain is about 80 amino acids and contains
the consensus sequence PRCXXPD. The exception to this rule is MMP23, in which
the critical cysteine is found within a distinct run of amino acids (Velasco et al.
1999
). The catalytic domain contains three conserved histidines in the sequence
HEXXHXXGXXH, which ligate the active site Zn
2+
. The glutamate residue within
the catalytic motif activates a zinc-bound H
2
O molecule providing the nucleophile
that cleaves peptide bonds.
The cysteine thiol and zinc ion interaction keeps proMMPs in a latent state, and
this linkage must be disrupted for the enzyme to gain catalytic activity (Van Wart
and Birkedal-Hansen
1990
). About one-third of MMPs, including all membrane-
bound MMPs, contain a furin-recognition sequence between the pro- and catalytic
domains and are activated intracellularly before secretion (Illman et al.
2003
; Kang
et al.
2002
; Pei and Weiss
1995
; Sato et al.
1996
). For the other MMPs, the mode of
activation is more presumed than proved, and as we have discussed in an earlier
review (Ra and Parks
2007
), the in vivo mechanism for the activation of most non-
furin cleaved proMMPs is unknown.
With the exceptions of MMP7, 23, and 26, MMPs have a flexible proline-rich
hinge region and a hemopexin-like C-terminal domain, which is thought to function
in interactions with other macromolecules, such as protein substrates or anchoring
factors. Other domains are restricted to subgroups of enzymes. For example, four
membrane-type MMPs (MMP14, 15, 16, and 24) have transmembrane and cyto-
solic domains, whereas MMP17 and 25 have C-terminal hydrophobic extensions
that act as a glycosylphosphatidylinositol (GPI) anchoring signal. The two gelati-
nases (MMP2 and MMP9) have gelatin-binding domains that resemble similar
motifs in fibronectin. In addition to a remarkably common 3D structure (Massova
et al.
1998
), MMPs share a similar gene arrangement suggesting that they arose by
duplications of an ancestor gene. At least eight of the known human MMP genes
