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Role of Glutaredoxin1 and Glutathione in regulating the activity of the copper-transporting P-type ATPases, ATP7A and ATP7B

Singleton, William C. J., McInnes, Kelly T., Cater, Michael A., Winnal, Wendy R., McKirdy, Ross, Yu, Yu, Taylor, Philip E., Ke, Bi-Xia, Richardson, Des R., Mercer, Julian.F.B and La Fontaine, Sharon 2010, Role of Glutaredoxin1 and Glutathione in regulating the activity of the copper-transporting P-type ATPases, ATP7A and ATP7B, Journal of biological chemistry, vol. 285, no. 35, pp. 27111-27121.

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Title Role of Glutaredoxin1 and Glutathione in regulating the activity of the copper-transporting P-type ATPases, ATP7A and ATP7B
Author(s) Singleton, William C. J.
McInnes, Kelly T.
Cater, Michael A.
Winnal, Wendy R.
McKirdy, Ross
Yu, Yu
Taylor, Philip E.
Ke, Bi-Xia
Richardson, Des R.
Mercer, Julian.F.B
La Fontaine, Sharon
Journal name Journal of biological chemistry
Volume number 285
Issue number 35
Start page 27111
End page 27121
Publisher American Society of Biological Chemists
Place of publication Baltimore, Md.
Publication date 2010-08-27
ISSN 0021-9258
1083-351X
Summary The copper-transporting P-type ATPases (Cu-ATPases), ATP7A and ATP7B, are essential for the regulation of intracellular copper homeostasis. In this report we describe new roles for glutathione (GSH) and glutaredoxin1 (GRX1) in Cu homeostasis through their regulation of Cu-ATPase activity. GRX1 is a thiol oxidoreductase that catalyzes the reversible reduction of GSH-mixed disulfides to their respective sulfhydryls (deglutathionylation).

Here, we demonstrated that glutathionylation of the Cu-ATPases and their interaction with GRX1 were affected by alterations in Cu levels. The data support our hypothesis that the Cu-ATPases serve as substrates for Cu-dependent GRX1-mediated deglutathionylation. This in turn liberates the Cu-ATPase cysteinyl thiol groups for Cu binding and transport. GSH depletion experiments led to reversible inhibition of the Cu-ATPases that correlated with effects on intracellular Cu levels and GRX1 activity. Finally, knockdown of GRX1 expression resulted in an increase in intracellular Cu accumulation. Together, these data directly implicate GSH and GRX1 with important new roles in redox regulation of the Cu-ATPases, through modulation of Cu binding by the Cu-ATPase cysteine motifs.
Language eng
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
HERDC collection year 2010
Copyright notice ©2010, The American Society for Biochemistry and Molecular Biology, Inc
Persistent URL http://hdl.handle.net/10536/DRO/DU:30034412

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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Created: Wed, 27 Apr 2011, 12:57:15 EST by Teresa Treffry