Radically Different Thioredoxin Domain Arrangement of ERp46, an Efficient Disulfide Bond Introducer of the Mammalian PDI Family
Radically Different Thioredoxin Domain Arrangement of ERp46, an Efficient Disulfide Bond Introducer of the Mammalian PDI Family
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DOI：
10.1016/j.str.2013.12.013
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发表时间：
2014-03-04
期刊：
影响因子：
5.7
通讯作者：
Inaba, Kenji
中科院分区：
文献类型：
--
作者：
Kojima, Rieko;Okumura, Masaki;Inaba, Kenji
哺乳动物内质网（ER）中含有多种氧化性蛋白质折叠网络，其中蛋白质二硫键异构酶（PDI）家族成员ERp 46与过氧化物氧还蛋白-4（Prx 4）一起作为二硫键的有效引入者。我们揭示了一个完全不同的分子结构的ERp 46，其中N-末端的两个硫氧还蛋白（Trx）结构域与带正电荷的补丁附近的肽结合位点和C-末端的Trx连接的异常长的环，并安排extendedly，形成一个开放的V形。而PDI催化天然二硫键的形成，通过两个相互面对的氧化还原活性位点的折叠中间体结合到中央裂缝的合作行动，ERp 46 Trx结构域是分开的，独立行动，并在早期的氧化蛋白质折叠过程中快速，但混杂的二硫键的形成。因此，多个PDI家族成员可能有助于氧化折叠的不同阶段，并协同工作以确保ER中多二硫键蛋白的有效产生。
The mammalian endoplasmic reticulum (ER) contains a diverse oxidative protein folding network in which ERp46, a member of the protein disulfide isomerase (PDI) family, serves as an efficient disulfide bond introducer together with Peroxiredoxin-4 (Prx4). We revealed a radically different molecular architecture of ERp46, in which the N-terminal two thioredoxin (Trx) domains with positively charged patches near their peptide-binding site and the C-terminal Trx are linked by unusually long loops and arranged extendedly, forming an opened V-shape. Whereas PDI catalyzes native disulfide bond formation by the cooperative action of two mutually facing redox-active sites on folding intermediates bound to the central cleft, ERp46 Trx domains are separated, act independently, and engage in rapid but promiscuous disulfide bond formation during early oxidative protein folding. Thus, multiple PDI family members likely contribute to different stages of oxidative folding and work cooperatively to ensure the efficient production of multi-disulfide proteins in the ER.