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Role of Matrix Metalloproteases in Degradation of ECM
Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential fo…
All tissues and cell types are surrounded by an extracellular matrix or ECM. So, degradation of ECM is necessary to make space for the cells to proliferate and migrate.
Cells do so by secreting matrix metalloproteases or MMPs, specialized enzymes which hydrolyze proteins and glycoproteins present in the ECM.
MMPs are a large family of proteins classified based on their substrate affinity, but all of them share several common features, such as an active site with three conserved histidine residues bound to a zinc ion. Additionally, most MMPs are active at neutral pH.
Collagenase, the most common MMP cleaves fibrillar collagen in two steps. First, collagenase unwinds the triple helical structure of collagen at a specific site and degrades the peptide bonds. This denatured collagen, called gelatin, is further degraded by gelatinase into smaller fragments.
However, the activity of MMPs must be tightly regulated to avoid unnecessary ECM degradation. For instance, cells produce specific protease inhibitors that can inhibit MMP activity when not required.
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Q1: What are matrix metalloproteases and why do cells need them?
Matrix metalloproteases (MMPs) are specialized enzymes that hydrolyze proteins and glycoproteins in the extracellular matrix. Cells secrete MMPs to degrade the ECM, creating space for cell proliferation and migration through the dense matrix network. This process is essential during embryonic development and tissue remodeling.
Q2: How do collagenases break down collagen molecules?
Collagenase, the most common MMP, cleaves fibrillar collagen in two steps. First, it unwinds the triple helical structure of collagen at a specific site and degrades the peptide bonds, producing denatured collagen called gelatin. Gelatinase then further degrades this gelatin into smaller fragments.
Q3: What structural features do all matrix metalloproteases share?
All MMPs share common structural features, including an active site with three conserved histidine residues bound to a zinc ion. Most MMPs are active at neutral pH. These conserved features allow MMPs to function as a large family of proteins classified by their substrate affinity.
Q4: How is MMP activity regulated in cells?
MMP activity is tightly regulated at multiple levels: gene expression control, mRNA half-life regulation, and post-synthesis regulation using proteases and inhibitors. Cells produce specific protease inhibitors to inhibit MMP activity when not required. MMPs are also regulated by cytokines, growth factors, corticosteroids, and other signaling molecules.
Q5: What physiological processes depend on matrix metalloprotease activity?
MMPs are essential for maintaining tissue homeostasis and play critical roles in bone remodeling, immunity, angiogenesis, and wound healing. During metamorphosis, collagenase activity enables tadpole tail remodeling and morphogenesis into adult body forms. MMP expression is normally maintained at low levels and modulated only when local tissue remodeling is required.
Q6: Why must matrix metalloprotease activity be carefully controlled?
Tight regulation of MMP activity prevents unnecessary and excessive ECM degradation that could damage tissue integrity. Uncontrolled MMP activity could compromise the structural support provided by the extracellular matrix. Cells use protease inhibitors and regulatory mechanisms to ensure MMPs function only when tissue remodeling is physiologically needed.
Q7: Which collagen types can collagenase enzymes degrade?
Collagenase molecules can cleave collagen types I, II, and III at a specific site approximately three-fourths distance from the N-terminal. Beyond these fibrillar collagens, collagenase also digests several other ECM and non-ECM molecules, demonstrating the broad substrate specificity of this important MMP.