The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family.
The general applicability of the "cysteine-switch" activation mechanism to the members of the matrix metalloproteinase (MMP) gene family is examined here. All 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.
Van Wart
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Department of Chemistry, Florida State University, Tallahassee 32306-3015.
Birkedal-Hansen
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D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D003012:Microbial Collagenase / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D015032:Zinc / Q000378:metabolism
D008666:Metalloendopeptidases; D003012:Microbial Collagenase; D015032:Zinc; D003545:Cysteine