Idoji Yoshiko, Watanabe Yuko, Yamashita Akifumi, Yamanishi Kyosuke, Nishiguchi Seiji, Shimada Kazunori, Yasunaga Teruo, Yamanishi Hiromichi
Hirakata Ryoikuen, Tsudahigashi 2-1-1, Hirakata, Osaka 573-0122, Japan.
Int J Mol Med. 2008 Apr;21(4):461-8.
Since whey-acidic-protein domain (WAP) containing protease inhibitors such as SLPI (secretory leukocyte protease inhibitor) and elafin (elastase-specific inhibitor) have antimicrobial activities and are thought to play critical roles in mucosal defenses, we are interested in these protease inhibitors. By accessing the Novartis mouse expression database, we found that the four WAP family members, SLPI, WFDC2, WFDC5, and WFDC12, are highly expressed in the oral organs, such as the trachea, tongue, and salivary glands. Since their WAP domains play pivotal roles in the antimicrobial and/or antiprotease activities and their application in therapeutics are expected to have practical value, we collected 98 WAP homologues and tried to predict their physiological functions by analyzing their amino acid sequence structures. From the multiple alignments of amino acid sequences, we predicted that most of the mammalian N-terminal WAP domains derived from SLPIs and the WAP domains derived from WFDC12s have antimicrobial activities, whereas most of the mammalian C-terminal WAP domains derived from SLPIs and the WAP domains derived from elafins have antiprotease activities. From the phylogenetic tree, it was revealed that an ancestral WAP protein initially diverged into the WFDC5-C WAP domain and the ancestral protein for the other WAP domains. Subsequently, the ancestral protein for the other WAP domains diverged into two ancestral proteins, one for elafin and SLPI-C WAP domains and the other, for SLPI-N, WFDC15b, WFDC12, and WFDC5-N WAP domains, respectively. Moreover, the tree indicated that the WFDC5-N and WFDC12 WAP domains share a common ancestral protein.
由于含有诸如分泌型白细胞蛋白酶抑制剂（SLPI）和弹性蛋白酶特异性抑制剂（elafin）等蛋白酶抑制剂的乳清酸性蛋白结构域（WAP）具有抗菌活性，并被认为在黏膜防御中发挥关键作用，因此我们对这些蛋白酶抑制剂很感兴趣。通过访问诺华小鼠表达数据库，我们发现四个WAP家族成员，即SLPI、WFDC2、WFDC5和WFDC12，在口腔器官如气管、舌头和唾液腺中高度表达。由于它们的WAP结构域在抗菌和/或抗蛋白酶活性中起关键作用，并且预期它们在治疗中的应用具有实际价值，我们收集了98个WAP同源物，并试图通过分析它们的氨基酸序列结构来预测其生理功能。从氨基酸序列的多重比对中，我们预测大多数源自SLPI的哺乳动物N端WAP结构域和源自WFDC12的WAP结构域具有抗菌活性，而大多数源自SLPI的哺乳动物C端WAP结构域和源自elafin的WAP结构域具有抗蛋白酶活性。从系统发育树中可以看出，一个祖先WAP蛋白最初分化为WFDC5 - C WAP结构域和其他WAP结构域的祖先蛋白。随后，其他WAP结构域的祖先蛋白又分别分化为两个祖先蛋白，一个是elafin和SLPI - C WAP结构域的祖先蛋白，另一个是SLPI - N、WFDC15b、WFDC12和WFDC5 - N WAP结构域的祖先蛋白。此外，该树表明WFDC5 - N和WFDC12 WAP结构域共享一个共同的祖先蛋白。
