National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Antioxid Redox Signal. 2013 Jul 1;19(1):36-45. doi: 10.1089/ars.2012.4630. Epub 2012 Jul 9.
Human protein disulfide isomerase (hPDI) is a key enzyme and a redox-regulated chaperone responsible for oxidative protein folding in the endoplasmic reticulum. This work aims to reveal the molecular mechanism underlying the redox-regulated functions of hPDI by determining the crystal structures of hPDI in different redox states.
The structures of hPDI (abb'xa') in both the reduced and oxidized states showed that the four thioredoxin domains of a, b, b', and a' are arranged as a horseshoe shape with two CGHC active sites, respectively, in domains a and a' facing each other at the two ends. In reduced hPDI, domains a, b, and b' line up in the same plane, whereas domain a' twists ∼45° out. The two active sites are 27.6 Å apart. In oxidized hPDI, the four domains are differently organized to stay in the same plane, and the distance between the active sites increases to 40.3 Å. In contrast to the closed conformation of reduced hPDI, oxidized hPDI exists in an open state with more exposed hydrophobic areas and a larger cleft with potential for substrate binding.
This is the first report of the high-resolution structures of hPDI containing all four domains in both the reduced and the oxidized states. It reveals the redox-regulated structural dynamic properties of the protein.
The redox-regulated open/closed conformational switch of hPDI endows the protein with versatile target-binding capacities for its enzymatic and chaperone functions.
人蛋白二硫键异构酶（hPDI）是一种关键酶和氧化还原调节伴侣，负责内质网中氧化蛋白质折叠。本研究旨在通过确定不同氧化还原状态下 hPDI 的晶体结构，揭示 hPDI 氧化还原调节功能的分子机制。
还原态和氧化态 hPDI（abb'xa'）的结构表明，a、b、b'和 a'的四个硫氧还蛋白结构域排列成马蹄形，分别在结构域 a 和 a'的两端有两个 CGHC 活性位点相对。在还原态 hPDI 中，a、b 和 b' 排列在同一平面上，而 a' 扭曲约 45°。两个活性位点之间的距离为 27.6 Å。在氧化态 hPDI 中，四个结构域以不同的方式组织在一起，保持在同一平面上，活性位点之间的距离增加到 40.3 Å。与还原态 hPDI 的封闭构象相反，氧化态 hPDI 存在于开放状态，具有更多暴露的疏水区和潜在的底物结合的更大裂隙。
这是第一个报道包含还原态和氧化态所有四个结构域的 hPDI 的高分辨率结构的报告。它揭示了该蛋白氧化还原调节的结构动态特性。
hPDI 的氧化还原调节的开放/闭合构象转换赋予了该蛋白多种靶结合能力，用于其酶和伴侣功能。
