Substrate specificity of the oxidoreductase ERp57 is determined primarily by its interaction with calnexin and calreticulin.
Substrate specificity of the oxidoreductase ERp57 is determined primarily by its interaction with calnexin and calreticulin.
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DOI：
10.1074/jbc.m808054200
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发表时间：
2009-01-23
期刊：
影响因子：
--
通讯作者：
Bulleid NJ
中科院分区：
文献类型：
--
作者：
Jessop CE;Tavender TJ;Watkins RH;Chambers JE;Bulleid NJ
进入分泌途径的蛋白质内二硫键的形成由内质网定位的氧化还原酶的蛋白质二硫键异构酶家族催化。一种这样的酶，ERp57，被认为是催化非天然二硫键的异构化形成的糖蛋白与非结构化的富含二硫键的结构域。在这里，我们研究了ERp57对糖蛋白底物的特异性和ERp57和钙连接蛋白循环正确折叠的相互依赖性的机制。 我们的研究结果清楚地表明，ERp57必须与钙连接蛋白循环物理相关，以催化异构化反应与其大多数底物。此外，一些糖蛋白如果进入钙连接蛋白循环，则仅需要ERp57来正确形成二硫键。因此，ER氧化还原酶的特异性不仅由酶和底物的物理结合决定，而且还由辅助因子决定，例如在ER p57的情况下的钙连接蛋白和钙网蛋白。这些结论表明，钙连接蛋白循环已经进化出一个专门的氧化还原酶，以促进天然二硫键形成复杂的糖蛋白。
The formation of disulfides within proteins entering the secretory pathway is catalyzed by the protein disulfide isomerase family of endoplasmic reticulum localized oxidoreductases. One such enzyme, ERp57, is thought to catalyze the isomerization of non-native disulfide bonds formed in glycoproteins with unstructured disulfide-rich domains. Here we investigated the mechanism underlying ERp57 specificity toward glycoprotein substrates and the interdependence of ERp57 and the calnexin cycle for their correct folding. Our results clearly show that ERp57 must be physically associated with the calnexin cycle to catalyze isomerization reactions with most of its substrates. In addition, some glycoproteins only require ERp57 for correct disulfide formation if they enter the calnexin cycle. Hence, the specificity of ER oxidoreductases is not only determined by the physical association of enzyme and substrate but also by accessory factors, such as calnexin and calreticulin in the case of ERp57. These conclusions suggest that the calnexin cycle has evolved with a specialized oxidoreductase to facilitate native disulfide formation in complex glycoproteins.