Document Detail


Molecular bases of cyclic and specific disulfide interchange between human ERO1alpha protein and protein-disulfide isomerase (PDI).
MedLine Citation:
PMID:  21398518     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the endoplasmic reticulum (ER) of human cells, ERO1α 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 ERO1α is essential to avoid ER hyperoxidation. To investigate how ERO1α 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 β-hairpin of ERO1α 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. ERO1α associated preferentially with reduced PDI, explaining the stepwise disulfide shuttle mechanism, first from ERO1α to PDI and then from oxidized PDI to an unfolded polypeptide bound to its hydrophobic pocket. The interaction of ERO1α with ERp44, another PDI family member protein, was also analyzed. Notably, ERO1α-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 ERO1α activity may suggest its physiological role in ER redox and protein homeostasis.
Authors:
Shoji Masui; Stefano Vavassori; Claudio Fagioli; Roberto Sitia; Kenji Inaba
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2011-07-01     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16261-71     Citation Subset:  IM    
Affiliation:
Division of Protein Chemistry, Post-Genome Science Center, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Catalysis
Disulfides / chemistry*,  metabolism
Humans
Membrane Glycoproteins / chemistry*,  genetics,  metabolism
Membrane Proteins / chemistry,  genetics,  metabolism
Molecular Chaperones / chemistry,  genetics,  metabolism
Oxidation-Reduction
Oxidoreductases / chemistry*,  genetics,  metabolism
Protein Disulfide-Isomerases / chemistry*,  genetics,  metabolism
Protein Folding*
Protein Structure, Secondary
Chemical
Reg. No./Substance:
0/Disulfides; 0/ERP44 protein, human; 0/Membrane Glycoproteins; 0/Membrane Proteins; 0/Molecular Chaperones; EC 1.-/ERO1L protein, human; EC 1.-/Oxidoreductases; EC 5.3.4.1/Protein Disulfide-Isomerases
Comments/Corrections

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