Molecular Bases of Cyclic and Specific Disulfide Interchange between Human ERO1α Protein and Protein-disulfide Isomerase (PDI)

被引:63
作者
Masui, Shoji [1 ]
Vavassori, Stefano [2 ]
Fagioli, Claudio [2 ]
Sitia, Roberto [2 ]
Inaba, Kenji [1 ]
机构
[1] Kyushu Univ, Med Inst Bioregulat, Postgenome Sci Ctr, Div Prot Chem,Higashi Ku, Fukuoka 8128582, Japan
[2] Univ Vita Salute, San Raffaele Sci Inst, Div Genet & Cell Biol, I-20132 Milan, Italy
关键词
ENDOPLASMIC-RETICULUM; BOND FORMATION; GENERATING DISULFIDES; MISFOLDED PROTEINS; OXIDATIVE ACTIVITY; CRYSTAL-STRUCTURE; PEROXIREDOXIN-IV; HUMAN-CELLS; ERP44; FAMILY;
D O I
10.1074/jbc.M111.231357
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
In the endoplasmic reticulum (ER) of human cells, ERO1 alpha and protein-disulfide isomerase (PDI) constitute one of the major electron flow pathways that catalyze oxidative folding of secretory proteins. Specific and limited PDI oxidation by ERO1 alpha is essential to avoid ER hyperoxidation. To investigate how ERO1 alpha oxidizes PDI selectively among more than 20 ER-resident PDI family member proteins, we performed docking simulations and systematic biochemical analyses. Our findings reveal that a protruding beta-hairpin of ERO1 alpha specifically interacts with the hydrophobic pocket present in the redox-inactive PDI b'-domain through the stacks between their aromatic residues, leading to preferred oxidation of the C-terminal PDI a'-domain. ERO1 alpha associated preferentially with reduced PDI, explaining the stepwise disulfide shuttle mechanism, first from ERO1 alpha to PDI and then from oxidized PDI to an unfolded polypeptide bound to its hydrophobic pocket. The interaction of ERO1 alpha with ERp44, another PDI family member protein, was also analyzed. Notably, ERO1 alpha-dependent PDI oxidation was inhibited by a hyperactive ERp44 mutant that lacks the C-terminal tail concealing the substrate-binding hydrophobic regions. The potential ability of ERp44 to inhibit ERO1 alpha activity may suggest its physiological role in ER redox and protein homeostasis.
引用
收藏
页码:16261 / 16271
页数:11
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