Staphostatins: an expanding new group of proteinase inhibitors with a unique specificity for the regulation of staphopains, Staphylococcus spp. cysteine proteinases

Abstract

A novel type of cysteine proteinase inhibitor (SspC) has been recently recognized in Staphylococcus aureus (Massimi, I., Park, E., Rice, K., Muller-Esterl, W., Sauder, D.N., and McGavin, M.J. (2002) J Biol Chem 277: 41770-41777). In this paper we have identified homologous proteins encoded in the genome of S. aureus and other coagulase-negative Staphylococci. Collectively we refer to these proteins as staphostatins as they specifically inhibit cysteine proteinases (staphopains) from Staphylococcus spp. The primary structure of staphostatins seems to be unique, although they resemble cystatins in size (105-108 residues). Recombinant staphostatin A, a product of the scpB gene and staphostatin B (SspC) from S. aureus have been characterized in details. Similar to the cystatins, the staphostatins interact specifically with their target proteinases forming tight and stable non-covalent complexes, staphostatin A with staphopain A and staphostatin B with staphopain B. However, in contrast to the cystatins, each of which inhibits broad range of cathepsins, complex formation between staphostatin and staphopain appears to be exclusive, with no cross interaction observed. In addition, the activities of several tested cysteine proteinases of prokaryotic- and eukaryotic-origin were not affected by staphostatins. Such narrow specificity limited to staphopains is presumed to be required to protect staphylococcal cytoplasmic proteins from being degraded by prematurely activated/folded prostaphopains. This function is guaranteed through the unique co-expression of the secreted proteinase and the intracellular inhibitor from the same operon, and represents a unique mechanism of regulation of proteolytic activity in Gram-positive bacteria.