Structure and electron-transfer pathway of the human methionine sulfoxide reductase MsrB3

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)

[img] Text
216692.pdf - Published Version
Available under License Creative Commons Attribution.

676kB

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
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

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167070Engineering the CHO host cell to improve protein productionNeil BulleidBiotechnology and Biological Sciences Research Council (BBSRC)BB/K501864/1Institute of Molecular, Cell & Systems Biology