The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family.

Abstract

The general applicability of the "cysteineswitch" activation mechanism to the members of the matrix metalloproteinase (M1"P) gene family is examined here. AU currently known members of the MMP gene family share the characteristic that they are synthesized in a latent, inactive, form. Recent evidence suggests that this latency in human fibroblast collagenase (HFC) is the result of formation of an intramolecular complex between the single cysteine residue in its propeptide domain and the essential zinc atom in the catalytic domain, a complex that blocks the active site. Latent HFC can be activated by multiple means, all of which effect the dissociation of the cysteine residue from the complex. This is referred to as the "cysteine-switch" mechanism of activation. The propeptide domain that contains the critical cysteine residue and the catalytic domain that contains the zinc-binding site are the only two domains common to all of the MMPs. The amino acid sequences surrounding both the critical cysteine residue and a region of the protein chains containing two of the putative histidine zinc-binding ligands are highly conserved in all of the MMPs. A survey of the literature shows that many of the individual MMPs can be activated by the multiple means observed for latent HFC. These observations support the view that the cysteine-switch mechanism is applicable to all members of this gene family. This mechanism is unprecedented in enzymology as far as we know and offers the opportunity for multiple modes of physiological activation of these important enzymes. Since conditions in different cells and tissues may match those necessary to effect one of these activation modes for a given MMP, this may offer metabolic flexibility in the control of MMP activation.The matrix metalloproteinases (MMPs) are a family of enzymes secreted by resident and inflammatory cells that are collectively capable of degrading most or all of the constituent macromolecules of the extracellular matrix (1, 2). Although the conserved domains ofthe MMPs are homologous, these enzymes exhibit considerable diversity in their domain structures and protein substrate specificities. In spite of this diversity, the MMPs share several key characteristics. First, all members of this family are believed to be zinc proteinases (3)(4)(5)(6). Second, all of the MMPs are inhibited by tissue inhibitors of metalloproteinase, ubiquitous natural inhibitors which form inactive 1:1 complexes with these enzymes.

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

“…Unexposed cells gave MMP-2 gelatinolytic band with an apparent relative molecular mass of 62 kDa ( Figure 3A), indicating that the enzyme was constitutively secreted and readily activated (Van Wart and Birkedal-Hansen, 1990). In this form, MMP-2 persisted in CM even after exposure to NAMI-A, but its secretion declined significantly at 20 mM and further at 40 mM ( Figure 3B).…”

Matrix metalloproteinases in neuroinflammation

“…Proteolytic removal or reconfiguration of the propeptide region activates the enzymes. Exposure of the catalytic site is referred to as the "cysteine switch" (Van Wart and Birkedal Hansen, 1990). Gelatinase A (MMP-2) is a constitutively expressed molecule with a molecular weight of 72 kDa; it is normally present in brain tissue and in the cerebrospinal fluid (CSF).…”

Matrix remodeling during endochondral ossification

“…Surprisingly, humans in whom both MMP2 alleles are mutated display an osteolysis and arthritis syndrome typified by destruction and resorption of affected bones [35], similar to the phenotype of MT1-MMP −/− mice [8,9] described below. Although an abnormal bone phenotype has not been described in MMP2 −/− mice [36], studies using different strains of mice are required as severity of bone phenotypes might be strain dependent.The membrane localization of MT-MMPs makes them particularly suitable for pericellular proteolysis [10]. Among the six MT-MMPs identified, MT1-MMP is highly expressed in embryonic skeletal and periskeletal tissues [16,37]; similar to MMP9, its expression is particularly high in osteoclast precursors, osteoclasts and chondroclastic cells [38].…”