Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity
Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity
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DOI：
10.1515/hsz-2014-0140
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发表时间：
2014-09-01
影响因子：
3.7
通讯作者：
Goettig, Peter
中科院分区：
文献类型：
--
作者：
Guo, Shihui;Skala, Wolfgang;Goettig, Peter
在蛋白质合成和转运到内质网的过程中，大多数钾化钾素相关肽酶（KLKs）在asn - xha - ser /Thr序列上与n-乙酰氨基葡萄糖(2)-甘糖糖(9)单元进行n-糖基化。这些n -聚糖在高尔基体中被修饰，其中在Ser和Thr上发生额外的o -糖基化，在细胞外释放klk到细胞外空间之前。序列存在于所有15个klk成员中，对天然和重组来源的klk的比较研究阐明了糖基化的某些方面。虽然哺乳动物klk1、3、4、6和8的糖基化已经被非常详细地分析，例如通过晶体结构，但各自的功能在很大程度上仍然不清楚。在某些情况下，观察到klk在糖基化后酶活性的改变。值得注意的是，与健康个体相比，在良性前列腺增生和前列腺癌样本中，KLK3/PSA的糖基化模式发生了变化。通过与其他糖基化蛋白及其调控的比较，可以推断出KLK糖基化在结构稳定、防止降解和底物特异性活性调节方面的潜在功能。根据蛋白质扇区的新概念，远离活性位点的糖基化可能会显著影响蛋白酶的活性。新的药理学方法可以在治疗的背景下利用工程聚糖。
Most kallikrein-related peptidases (KLKs) are N-glycosylated with N-acetylglucosamine(2)-mannose(9) units at Asn-Xaa-Ser/Thr sequons during protein synthesis and translocation into the endoplasmic reticulum. These N-glycans are modified in the Golgi machinery, where additional O-glycosylation at Ser and Thr takes place, before exocytotic release of the KLKs into the extracellular space. Sequons are present in all 15 members of the KLKs and comparative studies for KLKs from natural and recombinant sources elucidated some aspects of glycosylation. Although glycosylation of mammalian KLKs 1, 3, 4, 6, and 8 has been analyzed in great detail, e. g., by crystal structures, the respective function remains largely unclear. In some cases, altered enzymatic activity was observed for KLKs upon glycosylation. Remarkably, for KLK3/PSA, changes in the glycosylation pattern were observed in samples of benign prostatic hyperplasia and prostate cancer with respect to healthy individuals. Potential functions of KLK glycosylation in structural stabilization, protection against degradation, and activity modulation of substrate specificity can be deduced from a comparison with other glycosylated proteins and their regulation. According to the new concept of protein sectors, glycosylation distant from the active site might significantly influence the activity of proteases. Novel pharmacological approaches can exploit engineered glycans in the therapeutical context.