Javitt, G., Cao, Z., Resnick, E., Gabizon, R., Bulleid, N. and Fass, D. (2020) Structure and electron-transfer pathway of the human methionine sulfoxide reductase MsrB3. Antioxidants and Redox Signaling, 33(10), pp. 665-678. (doi: 10.1089/ars.2020.8037) (PMID:32517586) (PMCID:PMC7475093)
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Abstract
Introduction: The post-translational oxidation of methionine to methionine sulfoxide is a reversible process, enabling repair of oxidative damage to proteins and the use of sulfoxidation as a regulatory switch. Methionine sulfoxide reductases catalyze the stereospecific reduction of methionine sulfoxide. One of the mammalian methionine sulfoxide reductases, MsrB3, has a signal sequence for entry into the endoplasmic reticulum (ER). In the ER, MsrB3 is expected to encounter a distinct redox environment compared to its paralogs in the cytosol, nucleus, and mitochondria. Aims: We sought to determine the location and arrangement of MsrB3 redox-active cysteines, which may couple MsrB3 activity to other redox events in the ER. Results: We determined the human MsrB3 structure using X-ray crystallography. The structure revealed that a disulfide bond near the protein amino terminus is distant in space from the active site. Nevertheless, biochemical assays showed that these amino-terminal cysteines are oxidized by the MsrB3 active site after its reaction with methionine sulfoxide. Innovation: This study reveals a mechanism to shuttle oxidizing equivalents from the primary MsrB3 active site toward the enzyme surface, where they would be available for further dithiol-disulfide exchange reactions. Conclusion: Conformational changes must occur during the MsrB3 catalytic cycle to transfer oxidizing equivalents from the active site to the amino-terminal redox-active disulfide. The accessibility of this exposed disulfide may help couple MsrB3 activity to other dithiol/disulfide redox events in the secretory pathway.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Cao, Dr Zhenbo and Bulleid, Professor Neil |
Authors: | Javitt, G., Cao, Z., Resnick, E., Gabizon, R., Bulleid, N., and Fass, D. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Antioxidants and Redox Signaling |
Publisher: | Mary Ann Liebert, Inc. Publishers |
ISSN: | 1523-0864 |
ISSN (Online): | 1557-7716 |
Published Online: | 10 June 2020 |
Copyright Holders: | Copyright © 2020 Gabriel Javitt et al. |
First Published: | First published in Antioxidants and Redox Signaling 33(10): 665-678 |
Publisher Policy: | Reproduced under a Creative Commons License |
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