Document Detail


Functional partnership of the copper export machinery and glutathione balance in human cells.
MedLine Citation:
PMID:  22648419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cells use the redox properties of copper in numerous physiologic processes, including antioxidant defense, neurotransmitter biosynthesis, and angiogenesis. Copper delivery to the secretory pathway is an essential step in copper utilization and homeostatic maintenance. We demonstrate that the glutathione/glutathione disulfide (GSH/GSSG) pair controls the copper transport pathway by regulating the redox state of a copper chaperone Atox1. GSSG oxidizes copper-coordinating cysteines of Atox1 with the formation of an intramolecular disulfide. GSH alone is sufficient to reduce the disulfide, restoring the ability of Atox1 to bind copper; glutaredoxin 1 facilitates this reaction when GSH is low. In cells, high GSH both reduces Atox1 and is required for cell viability in the absence of Atox1. In turn, Atox1, which has a redox potential similar to that of glutaredoxin, becomes essential for cell survival when GSH levels decrease. Atox1(+/+) cells resist short term glutathione depletion, whereas Atox1(-/-) cells under the same conditions are not viable. We conclude that GSH balance and copper homeostasis are functionally linked and jointly maintain conditions for copper secretion and cell proliferation.
Authors:
Yuta Hatori; Sara Clasen; Nesrin M Hasan; Amanda N Barry; Svetlana Lutsenko
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-06     Completed Date:  2012-11-05     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  26678-87     Citation Subset:  IM    
Affiliation:
Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphatases / genetics,  physiology
Amino Acid Sequence
Biological Transport
Cation Transport Proteins / chemistry,  genetics,  physiology*
Cell Line
Copper / metabolism*
Glutathione / metabolism*
Glutathione Reductase / metabolism
Humans
Molecular Chaperones / chemistry,  physiology*
Oxidation-Reduction
Grant Support
ID/Acronym/Agency:
R01 DK071865/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/ATOX1 protein, human; 0/Cation Transport Proteins; 0/Molecular Chaperones; 70-18-8/Glutathione; 7440-50-8/Copper; EC 1.8.1.7/Glutathione Reductase; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.3.4/Wilson disease protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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