Structural Insights into the Redox-Regulated Dynamic Conformations of Human Protein Disulfide Isomerase

被引:169
作者
Wang, Chao [1 ,2 ]
Li, Wei [1 ]
Ren, Jinqi [1 ]
Fang, Jingqi [3 ]
Ke, Huimin [1 ]
Gong, Weimin [1 ]
Feng, Wei [1 ]
Wang, Chih-chen [1 ]
机构
[1] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
[2] Chinese Acad Sci, Grad Univ, Beijing 100101, Peoples R China
[3] Jilin Univ, Sch Pharmaceut Sci, Changchun 130023, Peoples R China
基金
中国国家自然科学基金;
关键词
BINDING SITE; B DOMAIN; CHAPERONE; REACTIVATION; HOMEOSTASIS; REGION; ERO1; A';
D O I
10.1089/ars.2012.4630
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aim: 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. Results: 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 similar to 45 degrees out. The two active sites are 27.6 angstrom 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 angstrom. 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. Innovation: 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. Conclusion: The redox-regulated open/closed conformational switch of hPDI endows the protein with versatile target-binding capacities for its enzymatic and chaperone functions.
引用
收藏
页码:44 / 53
页数:10
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