The matrix metalloproteinases
interact with a number of extracellular matrix molecules via discrete
functional domains. For example, a collagen binding domain
in MMP-2 is responsible for most of the interactions of the
enzyme with the collagen substrate molecules that it hydrolyses.
This collagen binding domain is composed of three modules with high
similarity to the type II
modules also present in the collagen binding domains of fibronectin. We have earlier
characterized the contribution of the collagen binding domain of MMP-2
to
interactions with several of its substrates (J.
Biol. Chem. 1995).
Importantly, this domain may also contribute importantly to the
positioning of the enzyme both in the extracellular matrix and on cell
surfaces. Therefore, we have investigated the role of the MMP-2
collagen binding domain in mediating enzyme interactions with
pericellular matrix molecules
and showed that it constitutes an additional mechanism for cell surface
positioning of the enzyme (J. Biol.
Chem., 1998). Continuing this line of research and to
further understand the molecular basis for collagen interactions with
fibronectin-like type II modules, we have analyzed and mapped
interactions of
recombinant proteins corresponding to different parts of the collagen
binding
region of fibronectin (Matrix Biology 2002). These experiments have enabled us to define the
relative importance of substrate size and binding to MMP-2 (Matrix
Biol. 2004), the functional basis for MMP-2 and MMP-9
ligand
interactions and substrate specificities (Biochemical J. 2005),
and the contribution of MMP-2 to cancer cell migration (Cancer
Res. 2005). Using peptide library screening, we have
identified an essential binding site for MMP-2 on type I collagen and
have used a collagen-derived peptide to specifically block MMP-2
interactions with collagen and block the cleavage of this substrate (Biochemical J. 2007).
Recently, we have engaged in detailed
studies of
the mechanism of fibronectin cleavage and the biology of
fibronectin fragments.
As
an integral part of ongoing funding from NIH (2001-2011), we are
pursuing our studies in interdisciplinary collaborative
efforts with
colleagues in the UTHSCSA Department
of Biochemistry, Center for
Biomolecular Structure
Analysis and Laboratory for Mass Spectrometry.
Matrix Metalloproteinases (MMPs) in
Health and Disease
We welcome collaborations, and in several collaborative efforts, we are investigating the roles of MMPs and matrix degradation in health and disease
Matrix molecules are degraded during
such conditions as periodontal disease, abnormal wound healing, and
cancer. We are
extending the observations on the fibronectin fragmentation in the
context of
wound healing with emphasis on the effects on cell behavior and cell
associated enzyme activation (Matrix Biology 2002 and Matrix Biology 2004). To
understand the potential role of MMPs in
hydrolysis of fibronectin, we are applying modern proteomics technics
to
explore the protein-MMP interactions.
To investigate the roles of MMPs
and matrix degradation in altered
wound healing in diabetes, we
have developed an active interdisciplinary collaboration with
colleagues in
UTHSCSA* Department of Orthopedics, Division of Podiatry and
Texas
Diabetes Institute, a facility devoted to management of patients
with diabetes in San Antonio and South Texas. We are
analyzing samples from patients suffering from diabetes
mellitus, who are particularly prone to poorly healing wounds and
extensive periodontal disease. Funding
for this effort has been granted from the South Texas Health Research
Center.
To enhance our analysis of
patient samples, we are integrating analyses with state-of-the art
techniques to quantify
enzyme activities in biological fluids.
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