Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Biol Chem. 2011 May;392(5):483-9. doi: 10.1515/BC.2011.044.
Bacterial proteases are considered virulence factors and it is presumed that by abrogating their activity, host endogenous protease inhibitors play a role in host defense against invading pathogens. Here we present data showing that Staphylococcus aureus cysteine proteases (staphopains) are efficiently inhibited by Squamous Cell Carcinoma Antigen 1 (SCCA1), an epithelial-derived serpin. The high association rate constant (k(ass)) for inhibitory complex formation (1.9×10(4) m/s and 5.8×10(4) m/s for staphopain A and staphopain B interaction with SCCA1, respectively), strongly suggests that SCCA1 can regulate staphopain activity in vivo at epithelial surfaces infected/colonized by S. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same for serpin interaction with target serine proteases whereby the formation of a covalent complex result in cleavage of the inhibitory reactive site peptide bond and associated release of the C-terminal serpin fragment. Interestingly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of native S. aureus-derived inhibitors of the staphopains (staphostatins). Given that S. aureus is a major pathogen of epithelial surfaces, we suggest that SCCA1 functions to temper the virulence of this bacterium by inhibiting the staphopains.
细菌蛋白酶被认为是毒力因子，据推测，通过消除它们的活性，宿主内源性蛋白酶抑制剂在宿主防御入侵病原体中发挥作用。在这里，我们提供的数据表明，金黄色葡萄球菌半胱氨酸蛋白酶（葡萄球菌蛋白酶）被鳞状细胞癌抗原 1（SCCA1）有效抑制，SCCA1 是一种上皮衍生的丝氨酸蛋白酶抑制剂。抑制复合物形成的高缔合速率常数（k（ass））（葡萄球菌蛋白酶 A 和葡萄球菌蛋白酶 B 分别与 SCCA1 相互作用的 k（ass）分别为 1.9×10（4）m/s 和 5.8×10（4）m/s），强烈表明 SCCA1 可以在金黄色葡萄球菌感染/定植的上皮表面调节葡萄球菌蛋白酶的活性。SCCA1 抑制葡萄球菌蛋白酶的机制显然与丝氨酸蛋白酶与靶标丝氨酸蛋白酶相互作用的机制相同，其中形成共价复合物导致抑制性反应性位点肽键的切割以及相关的 C 末端丝氨酸蛋白酶片段的释放。有趣的是，SCCA1 的反应性位点与天然金黄色葡萄球菌衍生的葡萄球菌蛋白酶抑制剂（葡萄球菌抑制剂）的反应性位点环中的一个基序非常相似。鉴于金黄色葡萄球菌是上皮表面的主要病原体，我们认为 SCCA1 通过抑制葡萄球菌蛋白酶来调节该细菌的毒力。
