Biomedical Engineering Reference
In-Depth Information
Figure 3
Inhibition of MMPs by TIMPs. The TIMP-1, -2, and -4 inhibit extracel-
lular MMP activity, as well as MT-MMPs. The TIMP-2 acts in conjunction with
MT1-MMP to act as a receptor for the proform of MMP-2. The TIMP-3 is bound
to heparin sulphate proteoglycans and acts as an inhibitor of ADAMs.
A. MMP Inhibition
Tissue inhibitors of metalloproteases inhibit most MMPs examined with the
exception of TIMP-1 that does not possess inhibitory activity towards mem-
brane type (MT) 1-MMP (75). Tissue inhibitors of metalloproteases are
secreted proteins, but may also be found at the cell surface in association
with membrane-bound proteins (73). However, TIMP-3 is sequestered to
the extracellular matrix where it binds to heparin-sulfate-containing proteo-
glycans (Fig. 3) (76). In addition, TIMP-3, and to a lesser extent TIMP-1,
can inhibit members of the ADAMs family, e.g., TIMP-3 can inhibit
ADAM-17 (TACE), whereas TIMP-1 will inhibit ADAM-10 (77,78). The
first structure determinations of TIMP-MMP interactions came following
X-ray crystallographic studies of the TIMP-1-MMP-3 and TIMP-2-MT1-
MMP complexes (79,80). Crystallographic studies have shown that
TIMP-1 is a wedge-shaped molecule with an exposed ridge structure that
inserts into the catalytic site and substrate-binding groove of MMP-3.
Mutagenesis studies have revealed that residues situated in and around Cysl
and Cys70, which are disulfide-bonded in TIMP-1, are necessary for binding
to MMPs (81). In particular, Cys1 to Val4 and Met66 to Val69 form most of
the protein-protein interaction sites with MMP-3. Cys1 to Val4 bind to the
active site of the MMP, and Ser68 and Val69 fit into the substrate binding
sites. The
a
-amino and carbonyl groups of Cys1 bidentately co-ordinate the
catalytic Zn
2
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of the MMP, and the side chain of Thr2 extends into the large
substrate specificity pocket of MMP-3. Binding of TIMP-1 to MMP-3
