InterPro domain: IPR033739

Sequences having this domain are extracellular metalloproteases, such as collagenase and stromelysin, which degrade the extracellular matrix, are known as matrixins. They are zinc-dependent, calcium-activated proteases synthesised as inactive precursors(zymogens), which are proteolytically cleaved to yield the active enzyme [ 1 , 2 ].

All MMPs possess an N-terminal domain and a zinc-binding catalytic domain. The N-terminal domain peptide, cleaved during the activation step, includes a conserved PRCGVPDV octapeptide, known as the cysteine switch, whose Cys residue chelates the active site zinc atom, rendering the enzyme inactive [ 3 , 4 ]. The catalytic domain contains a zinc ion, which is responsible for the peptide hydrolysis reaction. Another zinc ion and one to three calcium ions are present in the catalytic domain with a structural role [ 5 ]. All but two of the human MMPs (MMP-7 and MMP-26) also have a C-terminal hemopexin-like domain, and two MMPs (MMP-2 and MMP-9) contain fibronectin insertions into their catalytic domains [ 6 ].

This entry represents the matrix metalloproteinase (MMP) sub-family M10A catalytic domain. MMPs are responsible for a great deal of pericellular proteolysis of extracellular matrix and cell surface molecules, playing crucial roles in morphogenesis, cell fate specification, cell migration, tissue repair, tumorigenesis, gain or loss of tissue-specific functions, and apoptosis [ 7 , 8 , 9 , 10 , 11 ]. In many instances, they are anchored to cell membranes via trans-membrane domains, and their activity is controlled via TIMPs (tissue inhibitors of metalloproteinases) [ 12 , 13 , 14 , 15 ].

1. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J. Biol. Chem. 264, 17213-21
2. Early expression of a collagenase-like hatching enzyme gene in the sea urchin embryo. EMBO J. 9, 3003-12
3. Structure-function relationships in the collagenase family member transin. J. Biol. Chem. 263, 11892-9
4. Mutational analysis of the transin (rat stromelysin) autoinhibitor region demonstrates a role for residues surrounding the "cysteine switch". J. Biol. Chem. 266, 1584-90
5. Matrix metalloproteases: variations on a theme. Prog. Biophys. Mol. Biol. 70, 73-94
6. Crystal structure of the catalytic domain of human matrix metalloproteinase 10. J. Mol. Biol. 336, 707-16
7. The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. Front. Biosci. 11, 3081-95
8. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev. 22, 145-52
9. Matrix metalloproteinases in lung biology. Respir. Res. 2, 10-9
10. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ. Res. 89, 201-10
11. Metalloproteinases in biology and pathology of the nervous system. Nat. Rev. Neurosci. 2, 502-11
12. Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science 284, 1667-70
13. Matrix metalloproteinases: structures, evolution, and diversification. FASEB J. 12, 1075-95
14. Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. EMBO J. 17, 5238-48
15. Focalized proteolysis: spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr. Opin. Cell Biol. 8, 731-8