Mechanisms for Activating Cu- and Zn-Containing Superoxide Dismutase in the Absence of the CCS Cu Chaperone

Mechanisms for Activating Cu- and Zn-Containing Superoxide Dismutase in the Absence of the CCS Cu Chaperone

The Cu- and Zn-containing superoxide dismutase 1 (SOD1) largely obtains Cu in vivo by means of the action of the Cu chaperone CCS. Yet, in the case of mammalian SOD1, a secondary pathway of activation is apparent. Specifically, when human SOD1 is expressed in either yeast or mammalian cells that are...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 16; pp. 5964 - 5969
Main Authors: Carroll, Mark C., Girouard, Jody B., Ulloa, Janella L., Subramaniam, Jamuna R., Wong, Phillip C., Valentine, Joan Selverstone, Culotta, Valeria Cizewski, Fridovich, Irwin
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 20-04-2004
National Acad Sciences
Subjects:
Animals
Biochemistry
Biological Sciences
Cell growth
Cell Line
Copper - chemistry
Electrophoresis
Enzyme Activation
Enzymes
Fibroblasts
Gels
Glutathione - metabolism
Mice
Molecular Chaperones - metabolism
Molecular Chaperones - physiology
Molecules
Mutation
Plasmids
Proteins
Saccharomyces cerevisiae Proteins
Superoxide Dismutase - chemistry
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxides
Yeasts
Zinc - chemistry
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Summary:The Cu- and Zn-containing superoxide dismutase 1 (SOD1) largely obtains Cu in vivo by means of the action of the Cu chaperone CCS. Yet, in the case of mammalian SOD1, a secondary pathway of activation is apparent. Specifically, when human SOD1 is expressed in either yeast or mammalian cells that are null for CCS, the SOD1 enzyme retains a certain degree of activity. This CCS-independent activity is evident with both wild-type and mutant variants of SOD1 that have been associated with familial amyotrophic lateral sclerosis. We demonstrate here that the CCS-independent activation of mammalian SOD1 involves glutathione, particularly the reduced form, or GSH. A role for glutathione in CCS-independent activation was seen with human SOD1 molecules that were expressed in either yeast cells or immortalized fibroblasts. Compared with mammalian SOD1, the Saccharomyces cerevisiae enzyme cannot obtain Cu without CCS in vivo, and this total dependence on CCS involves the presence of dual prolines near the C terminus of the SOD1 polypeptide. Indeed, the insertion of such prolines into human SOD1 rendered this molecule refractory to CCS-independent activation. The possible implications of multiple pathways for SOD1 activation are discussed in the context of SOD1 evolutionary biology and familial amyotrophic lateral sclerosis.
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Present address: Department of Biological Sciences and Bioengineering, India Institute of Technology, Kanpur, India.
Abbreviations: SOD1, superoxide dismutase 1; CCS, Cu chaperone for SOD1; FALS, familial amyotrophic lateral sclerosis; GSH, reduced glutathione; GSH1, γ-glutamyl cysteine synthetase 1; BSO, buthionine sulfoximine.
To whom correspondence should be addressed at: 615 North Wolfe Street, Room 7032, Baltimore, MD 21205. E-mail: vculotta@jhsph.edu.
This paper was submitted directly (Track II) to the PNAS office.
Edited by Irwin Fridovich, Duke University Medical Center, Durham, NC, and approved February 24, 2004
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0308298101