Prion protein glycosylation is sensitive to redox change
Prion protein glycosylation is sensitive to redox change
复制标题
DOI：
10.1074/jbc.274.49.34846
复制
发表时间：
1999-12-03
影响因子：
4.8
通讯作者：
Petersen, RB
中科院分区：
文献类型：
--
作者：
Capellari, S;Zaidi, SIA;Petersen, RB
在Pron疾病的发展过程中，将可溶的Prion蛋白转化为不溶的、致病的、抗蛋白酶的亚型是一个关键事件。尽管这种转换产生致病事件的机制尚不清楚，但越来越多的证据表明，这可能取决于Pron蛋白在防止氧化损伤方面的功能。因此，在这项研究中，我们评估了氧化还原敏感型半胱氨酸、糖基化和蛋白代谢之间的相互关系。用硫代还原剂二硫苏糖醇处理细胞，以评估细胞氧化状态对Pron蛋白合成的影响。氧化还原平衡的这种变化影响了普恩蛋白的糖基化，导致糖基化形式的唯一产生。通过突变参与其形成的半胱氨酸残基，证实了单个二硫键在普恩蛋白中调节这一效应的作用。这些数据表明，提高二硫键形成速度的条件有利于未糖基化的普恩蛋白的形成。因此，由于Pron蛋白上的葡聚糖对其致病转化具有保护作用，细胞氧化还原状态的变化将有利于未糖化形式的产生，从而增加发生Pron疾病的风险。
The conversion of soluble prion protein into an insoluble, pathogenic, protease-resistant isoform is a key event in the development of prion diseases. Although the mechanism by which the conversion engenders a pathogenic event is unclear, there is increasing evidence to suggest that this may depend on the function of the prion protein in preventing oxidative damage. Therefore, in this study, we assessed the interrelationship between redox-sensitive cysteine, glycosylation, and prion metabolism. Cells were treated with a thioreductant, dithiothreitol, to assess the effect of the cellular oxidation state on the synthesis of the prion protein. This change in redox balance affected the glycosylation of the prion protein, resulting in the sole production of glycosylated forms. The role of the single disulfide bridge in mediating this effect within the prion protein was confirmed by mutating the cysteine residues involved in its formation. These data suggest that conditions that increase the rate of formation of the disulfide bridge favor formation of the unglycosylated prion protein. Thus, since the presence of glycans on the prion protein is protective against its pathogenic conversion, a change in the redox status of the cell would increase the risk of developing a prion disease by favoring the production of the unglycosylated form.