Cysteine switch

Latent forms of MMPs can be activated by mechanisms which cause the dissociation of the intramolecular complex between a particular cysteine residue and the required zinc metal ligand (a complex that blocks the active site) [47], This occurs because the cysteine of the latent enzyme is coordinated to the active site in a particular way that blocks the MMP active site. Collectively, the activation of MMPs occurs through a process which has been termed the cysteine-switch . Activators of the MMPs include proteases (e.g. plasmin), conformational perturbants (SDS, NaSCN), heavy metals and organomercurials (e.g. Au(I) compounds, Hg(II)), oxidants (e.g. OC1-), disulfide compounds (e.g. GSSG) and sulfhydryl alkylating agents (e.g. V-ethylmaleimide) [47 and refs, therein]. 

Rosenblum G, Meroueh S, Toth M, Fisher IF, Fridman R, Mobashery S, Sagi I. Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen challenging the cysteine switch dogma. J. Am. Chem. Soc. 2007 129 13566-13574. 

Grams, F., Huber, R., Kress, L.F., Moroder, L., and Bode, W. (1993). Activation of snake venom metalloproteinases by a cysteine switch-like mechanism. FEES Lett. 335 76-80. 

Van Wart, H.E. and Birkedal-Hansen, H. (1990). The cysteine switch A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl. Acad, Sci. USA 87 5578-5582. 

Fu, X., S. Y. Kassim, W. C. Parks, and J. W. Heinecke. 2001. Hypochlorons add oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 276(44) 41279-87. 

Paulsen CE, Carroll KS (2010) Orchestrating redox signaling networks through regulatory cysteine switches. ACS Chem Biol 5(l) 47-62. doi 10.1021/cb900258z... 

Human matrix metalloproteinases may be processed from their proenzyme forms to their active forms by two new and unique mechanisms (Maeda et al. 1998) Firstly, by bacterial proteases such as Pseudomonas elastase and Vibrio cholerae protease, which cleave off the N-terminal autoinhibitory domain (so-called cysteine switch) from pro-matrix metalloproteinases. The second mechanism depends on free radical generation by activated polymorphonuclear leucocytes. In this case, peroxyni-trite (ONOO") or nitrogen dioxide radical ("NOj) are the key reagents. 

Both O2 and NO are generated by activated macrophages and polymorphonuclear leucocytes as a result of immunologic responses involving various proinflammatory cytokines. NOj or ONOO" seems to interact with a single cysteine residue in the propeptide autoinhibitory domain, or so called cysteine-switch of pro-matrix metalloproteinases, thus transforming pro-matrix metalloproteinases into their active conformation. 

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