Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells
Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells
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DOI：
10.1038/47062
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发表时间：
1999-11-04
期刊：
影响因子：
64.8
通讯作者：
Helenius, A
中科院分区：
文献类型：
--
作者：
Molinari, M;Helenius, A
链内和链间二硫键的形成是内质网中大多数分泌蛋白和膜结合蛋白成熟的一个组成部分（1,2）。有证据表明，蛋白质二硫异构酶（PDI）超家族成员是二硫键适当氧化和异构化所需机制的一部分（3-6）。基于体外研究的模型预测，氧化还原酶与底物之间混合二硫键的形成是底物多肽中天然链内二硫键生成的中间环节(7)。这是否就是硫醇氧化还原酶在内质网内起作用的方式尚不清楚。也没有确定PDI超家族的许多成员中的哪一个与新合成的底物蛋白直接相互作用，因为在氧化蛋白折叠过程中，从未在哺乳动物内质网中观察到短暂的混合二硫化物（7,8）。在这里，我们描述了体内共翻译和翻译后蛋白质氧化的机制。我们发现内质网氧化还原酶PDI和ERp57直接参与二硫化物氧化和异构化，并与凝集素钙连联素和钙网蛋白一起，在哺乳动物细胞内质网糖蛋白折叠中起中心作用。
The formation of intra- and interchain disulphide bonds constitutes an integral part of the maturation of most secretory and membrane-bound proteins in the endoplasmic reticulum(1,2). Evidence indicates that members of the protein disulphide isomerase (PDI) superfamily are part of the machinery needed for proper oxidation and isomerization of disulphide bonds(3-6). Models based on in vitro studies predict that the formation of mixed disulphide bonds between oxidoreductase and substrate is intermediate in the generation of the native intrachain disulphide bond in the substrate polypeptide(7). Whether this is how thiol oxidoreductases work inside the endoplasmic reticulum is not clear. Nor has it been established which of the many members of the PDI superfamily interacts directly with newly synthesized substrate proteins, because transient mixed disulphides have never been observed in the mammalian endoplasmic reticulum during oxidative protein folding(7,8). Here we describe the mechanisms involved in co- and post-translational protein oxidation in vivo. We show that the endoplasmic-reticulum-resident oxidoreductases PDI and ERp57 are directly involved in disulphide oxidation and isomerization, and, together with the lectins calnexin and calreticulin, are central in glycoprotein folding in the endoplasmic reticulum of mammalian cells.