Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7
复制标题
DOI：
10.1515/bc.2008.075
复制
发表时间：
2008-06-01
影响因子：
3.7
通讯作者：
Goettig, Peter
中科院分区：
文献类型：
--
作者：
Debela, Mekdes;Beaufort, Nathalie;Goettig, Peter
人激肽释放酶相关肽酶（KLK）是在多种组织如前列腺、卵巢、乳腺、睾丸、脑和皮肤中表达的（糜）-胰蛋白酶样丝氨酸蛋白酶。虽然它们的生理功能仅得到部分阐明，但许多KLK似乎是有用的预后癌症标志物，其表达水平与癌症的不同阶段之间存在明显的相关性。在纯化“新型”重组KLK方面的最新进展允许解决KLK 4、KLK 5、KLK 6和KLK 7的晶体结构。沿着这些数据，酶动力学研究和扩展的底物特异性分析使我们了解了KLK 4、5、6和7的非引发侧底物偏好。特异性口袋S1-S4的形状和极性很好地解释了它们的底物偏好。KLK 4、5和6表现出胰蛋白酶样特异性，在底物的P1位置强烈偏好Arg。相比之下，KLK 7对Tyr显示出独特的胰凝乳蛋白酶样特异性，这在P2也是优选的。所有四种KLK对P3残基几乎没有特异性，并且倾向于接受P4处的疏水残基。有趣的是，对于KLK 4，5和7，观察到扩展的带电表面区域，其最有可能作为生理底物的外部位点。
Human kallikrein-related peptidases (KLKs) are (chymo)-trypsin-like serine proteinases that are expressed in a variety of tissues such as prostate, ovary, breast, testis, brain, and skin. Although their physiological functions have been only partly elucidated, many of the KLKs appear to be useful prognostic cancer markers, showing distinct correlations between their expression levels and different stages of cancer. Recent advances in the purification of 'new type' recombinant KLKs allowed solution of the crystal structures of KLK4, KLK5, KLK6, and KLK7. Along with these data, enzyme kinetic studies and extended substrate specificity profiling have led to an understanding of the non-prime-side substrate preferences of KLK4, 5, 6, and 7. The shape and polarity of the specificity pockets S1-S4 explain well their substrate preferences. KLK4, 5, and 6 exhibit trypsin-like specificity, with a strong preference for Arg at the P1 position of substrates. In contrast, KLK7 displays a unique chymotrypsin-like specificity for Tyr, which is also preferred at P2. All four KLKs show little specificity for P3 residues and have a tendency to accept hydrophobic residues at P4. Interestingly, for KLK4, 5, and 7 extended charged surface regions were observed that most likely serve as exosites for physiological substrates.