27.8:
Role of Matrix Metalloproteases in Degradation of ECM
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.
27.8:
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 for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult body.
A collagenase molecule can cleave collagens type I, II, and III at a three-fourths distance from the N-terminal and digest several other ECM and non-ECM molecules.
The expression of MMPs is usually maintained at low levels in the body. Only when required, is MMP's activity modulated for local tissue remodeling. The activity of MMPs is regulated at several levels: regulation of gene expression, controlling the half-life of mRNA, and post-synthesis regulation, using other proteases and inhibitors. The MMPs are regulated by cytokines, growth factors, corticosteroids, retinoic acid, heparin, and interleukin-4.
MMPs help maintain tissue homeostasis and play an essential role in various physiological processes, such as bone remodeling, immunity, angiogenesis, and wound healing.
Suggested Reading
- Alberts, Bruce, et al. Molecular Biology of the Cell. 6th ed. Garland Science, 2017. Pp 1072.
- Lodish, Harvey, et al. Molecular Cell Biology. 8th ed. W.H. Freeman and Company, 2016. Pp 960
- Laronha, Helena, and Jorge Caldeira. "Structure and function of human matrix metalloproteinases." Cells 9, 2020: 1076.