Scott Fiona L, Sun Jiuru, Whisstock James C, Kato Keiko, Bird Phillip I
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
J Biochem. 2007 Oct;142(4):435-42. doi: 10.1093/jb/mvm156. Epub 2007 Aug 30.
SerpinB6 (Proteinase inhibitor 6/PI-6) is an intracellular serpin produced by leukocytes, platelets, endothelial cells, keratinocytes and other epithelial cells. It is a potent cathepsin G inhibitor thought to protect monocytes, neutrophils and bystander cells from ectopic cathepsin G during inflammation. Here we show that serpinB6 also inhibits the human serine protease kallikrein-8 (hK8) and that in human and mouse skin, serpinB6 and kallikrein-8 co-localize in differentiated keratinocytes. SerpinB6 inhibits hK8 with an association rate constant (kass) of 1.8 +/- 0.2 x 10(5) M(-1)s(-1) compared to 3.4 +/- 0.2 x 10(6) M(-1) s(-1) for the interaction between the mouse orthologue of serpinB6 (SPI3/serpinb6a) and mouse kallikrein-8 (mK8). Molecular modelling suggested that the lower efficiency of the serpinB6/hK8 interaction is partly due to the bulkier P2 methionine residue of serpinB6 compared to the smaller P2 valine in SPI3. Taken together, these results suggest that serpinB6 is a physiologically relevant inhibitor of hK8 in skin. We postulate that serpinB6 protects the intracellular compartment of keratinocytes from ectopic hK8.
丝氨酸蛋白酶抑制剂B6（蛋白酶抑制剂6/PI-6）是一种由白细胞、血小板、内皮细胞、角质形成细胞和其他上皮细胞产生的细胞内丝氨酸蛋白酶抑制剂。它是一种有效的组织蛋白酶G抑制剂，被认为在炎症过程中保护单核细胞、中性粒细胞和旁观者细胞免受异位组织蛋白酶G的侵害。在此我们表明，丝氨酸蛋白酶抑制剂B6还能抑制人丝氨酸蛋白酶激肽释放酶-8（hK8），并且在人和小鼠皮肤中，丝氨酸蛋白酶抑制剂B6和激肽释放酶-8在分化的角质形成细胞中共定位。丝氨酸蛋白酶抑制剂B6抑制hK8的缔合速率常数（kass）为1.8±0.2×10⁵ M⁻¹s⁻¹，而丝氨酸蛋白酶抑制剂B6的小鼠同源物（SPI3/丝氨酸蛋白酶抑制剂b6a）与小鼠激肽释放酶-8（mK8）相互作用的缔合速率常数为3.4±0.2×10⁶ M⁻¹ s⁻¹。分子模拟表明，丝氨酸蛋白酶抑制剂B6/hK8相互作用效率较低的部分原因是与SPI3中较小的P2缬氨酸相比，丝氨酸蛋白酶抑制剂B6的P2甲硫氨酸残基更大。综上所述，这些结果表明丝氨酸蛋白酶抑制剂B6是皮肤中hK8的生理相关抑制剂。我们推测丝氨酸蛋白酶抑制剂B6保护角质形成细胞的细胞内区室免受异位hK8的侵害。
