November 3, 2008
Matrix Remodeling Metalloproteinases and cancer cell invasion
Some test is taken verbatim from the literature cited
(Nagase et al (2006) Structure and function of matrix
metalloproteinases and TIMPs Cardiovascular Research
Based on domain organization and substrate preference,
are grouped into collagenases, gelatinases, stromelysins,
matrilysins, membrane-type (MT)-MMPs and others.
The focus the lecture is on
collagenases and gelatinases.
Degraded collagen is referred as gelatin.
cleave intact collagen molecules, whereas gelatinases cleavage degraded collagens.
Collagenases (MMP-1 and MT1-MMP) cleave interstitial collagens I, II and III
into characteristic ¾ and ¼ fragments (a single cleavage site in the C-terminus), but can
also digest other ECM molecules and soluble proteins.
Once cleaved, the digested
collagen is referred to as gelatin, which is the target of gelatinases.
and MMP-9) readily digest gelatin with the help of three fibronectin type II repeats that
bind to gelatin/collagen.
They also digest a number of ECM molecules including type
IV, V and XI collagens, laminins, aggrecan core protein.
MT-MMPs in mammals include four type I transmembrane proteins and two
The focus will be on MT1-MMP.
In inactive proMMPs, the SH group of a cysteine residue in the prodomain
interacts with the catalytic zinc ion in the catalytic domain.
Activation requires the
removal of the prodomain, freeing the catalytic zinc atom.
Moreover, for some MMPs
(e.g. proMMP-1), the prodomain interacts with the Hemopexin domain, rendering it in a
“closed” configuration in contrast to the “open” configuration of the active MMPs.
change in configuration is considered to create the collagen binding site.
Tissue Inhibitors of Metalloproteinases-TIMPs
(Rapi et al (2006)
The activity of various MMPs are controlled at the protein level via inhibition and
activation by the following four homologous tissue inhibitors of metalloproteinases
(TIMPs): TIMP-1, -2, -3, and -4.
TIMPs inhibit the MMPs in a 1:1 stoichiometry by
tightly binding to the active site of the enzyme primarily through their N-terminal
All four TIMPs inhibit active forms of most of the MMPs, but some
differences in their inhibitory properties have been reported.
For example, TIMP-2,
TIMP-3 and TIMP-4 are effective inhibitors of MT-MMPs, whereas TIMP-1 is a very
poor inhibitor of these enzymes.
TIMP-1 is an effective inhibitor of soluble MMPs.
Vu and Werb (2000) Matrix metalloproteinases: effectors of development and
Genes & Development 14:2123-2133
The MMP family of extracellular proteinases regulated development and physiologic
Genetic analyses using transgenic mice that have gain and loss of function of