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Chem Biol. 2008 Sep 22;15(9):960-8. doi: 10.1016/j.chembiol.2008.07.021.

The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS.

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Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, University Hospital, Lund, Sweden.


Human cystatin C is considered the physiologically most important inhibitor of endogenous papain-like cysteine proteases. We present here an unexpected function of cystatin C. Instead of acting as an inhibitor, cystatin C acts as a facultative, endogenous cofactor for the papain-like IgG-cleaving enzyme IdeS of the human pathogen Streptococcus pyogenes. IdeS activity is not dependent on cystatin C, but is significantly enhanced in the presence of cystatin C. We report a protease inhibitor that accelerates the activity of its putative target protease and a unique example of how a host protease inhibitor is "hijacked" by a bacterial protease to increase its activity. This finding has important implications for the view on protease-inhibitor interactions, and is relevant to consider in the therapeutic use of protease inhibitors.

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