Oxidative Modification to Cysteine Sulfonic Acid of Cys111 in Human Copper-Zinc Superoxide Dismutase
Journal of Biological Chemistry Volume 282 Issue 49
Page 35933-35944
published_at 2007-10-03
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| File | |
| Title ( eng ) |
Oxidative Modification to Cysteine Sulfonic Acid of Cys111 in Human Copper-Zinc Superoxide Dismutase
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| Creator |
Fujikawa Noriko
Kato Shinsuke
Yoshihara Daisaku
Ookawara Tomomi
Eguchi Hironobu
Taniguchi Naoyuki
Suzuki Keiichiro
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| Source Title |
Journal of Biological Chemistry
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| Volume | 282 |
| Issue | 49 |
| Start Page | 35933 |
| End Page | 35944 |
| Abstract |
Copper-zinc superoxide dismutase (SOD1) plays a protective role against oxidative stress. On the other hand, recent studies suggest that SOD1 itself is a major target of oxidative damage and has its own pathogenicity in various neurodegenerative diseases, including familial amyotrophic lateral sclerosis. Only human and great ape SOD1s among mammals have the highly reactive free cysteine residue, Cys111, at the surface of the SOD1 molecule. The purpose of this study was to investigate the role of Cys111 in the oxidative damage of the SOD1 protein, by comparing the oxidative susceptibility of recombinant human SOD1 modified with 2-mercaptoethanol at Cys111 (2-ME-SOD1) to wild-type SOD1. Wild-type SOD1 was more sensitive to oxidation by hydrogen peroxide-generating fragments, oligomers, and charge isomers compared with 2-ME-SOD1. Moreover, wild-type SOD1, but not 2-ME-SOD1, generated an upper shifted band in reducing SDS-PAGE even by air oxidation. Using mass spectrometry and limited proteolysis, this upper band was identified as an oxidized subunit of SOD1; the sulfhydryl group (Cys-SH) of Cys111 was selectively oxidized to cysteine sulfinic acid (Cys-SO2H) and to cysteine sulfonic acid (Cys-SO3H). The antibody raised against a synthesized peptide containing Cys111-SO3H reacted with only the Cys111-peroxidized SOD1 by Western blot analysis and labeled Lewy bodylike hyaline inclusions and vacuole rims in the spinal cord of human SOD1-mutated amyotrophic lateral sclerosis mice by immunohistochemical analysis. These results suggest that Cys111 is a primary target for oxidative modification and plays an important role in oxidative damage to human SOD1, including familial amyotrophic lateral sclerosis mutants.
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| Descriptions |
This work was supported by Grants-in-aid for Scientific Research 17500242 and 19500313; a Hitech Research Center grant and the 21st Century Centers of Excellence program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and in part by a Grant for the Research Group on Development of Novel Therapeutics for ALS from the Ministry of Health, Labor and Welfare of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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| Language |
eng
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| Resource Type | journal article |
| Publisher |
The American Society for Biochemistry and Molecular Biology, Inc.
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| Date of Issued | 2007-10-03 |
| Rights |
This research was originally published in the Journal of Biological Chemistry. Noriko Fujiwara,Miyako Nakano, Shinsuke Kato, Daisaku Yoshihara, Tomomi Ookawara, Hironobu Eguchi, Naoyuki Taniguchi, and Keiichiro Suzuki. Oxidative Modification to Cysteine Sulfonic Acid of Cys111 in Human Copper-Zinc Superoxide Dismutase. J. Biol. Chem. 2007; 282(49):35933-35944. © the American Society for Biochemistry and Molecular Biology.
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| Publish Type | Version of Record |
| Access Rights | open access |
| Source Identifier |
[ISSN] 0021-9258
[ISSN] 1083-351X
[DOI] 10.1074/jbc.M702941200
[DOI] https://doi.org/10.1074/jbc.M702941200
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