Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides.
Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides.
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DOI：
10.1091/mbc.e15-05-0321
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发表时间：
2015-10-01
影响因子：
3.3
通讯作者：
Molinari M
中科院分区：
文献类型：
--
作者：
Pisoni GB;Ruddock LW;Bulleid N;Molinari M
哺乳动物ER包含PDI超家族的23个成员。其底物特异性在很大程度上是未知的。TMX1显示出对膜结合的、含半胱氨酸的多肽的偏好。内质网（ER）是真核细胞中分泌蛋白和膜蛋白成熟的场所。哺乳动物内质网的内腔含有>20个蛋白质二硫键异构酶（PDI）超家族成员，其确保形成正确的分子内和分子间二硫键组，作为蛋白质折叠过程的关键限速反应。PDI超家族的组分还可以促进错误折叠的多肽跨ER膜移位，用于ER相关降解（ERAD）。PDI家族成员的高冗余度的原因和一个或另一个优先接合所需的基底特征知之甚少。在这里，我们表明，TMX1，家庭的几个跨膜成员之一，形成与ER凝集素钙连接蛋白的功能复合物，并优先干预含半胱氨酸，膜相关蛋白的成熟过程中，而忽略相同的含半胱氨酸的胞外域，如果不锚定在ER膜。因此，TMX1是活细胞中拓扑特异性客户蛋白氧化还原催化剂的第一个例子。
The mammalian ER contains 23 members of the PDI superfamily. Their substrate specificity is largely unknown. TMX1 shows a preference for membrane-bound, cysteine-containing polypeptides. The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. The lumen of the mammalian ER contains >20 members of the protein disulfide isomerase (PDI) superfamily, which ensure formation of the correct set of intramolecular and intermolecular disulfide bonds as crucial, rate-limiting reactions of the protein folding process. Components of the PDI superfamily may also facilitate dislocation of misfolded polypeptides across the ER membrane for ER-associated degradation (ERAD). The reasons for the high redundancy of PDI family members and the substrate features required for preferential engagement of one or the other are poorly understood. Here we show that TMX1, one of the few transmembrane members of the family, forms functional complexes with the ER lectin calnexin and preferentially intervenes during maturation of cysteine-containing, membrane-associated proteins while ignoring the same cysteine-containing ectodomains if not anchored at the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst in living cells.