Structure and Electron-Transfer Pathway of the Human Methionine Sulfoxide Reductase MsrB3

• DOI: 10.1089/ars.2020.8037
• Publication Date: 2020-06-10T07:35:02Z
• Authors: Gabriel Javitt; Zhenbo Cao; Efrat Resnick; Ronen Gabizon; Neil J. Bulleid; Deborah Fass
• Keywords: Methionine sulfoxide reductase; Methionine sulfoxide; MSRA; Dithiol

Aims: The post-translational oxidation of methionine to sulfoxide (MetSO) is a reversible process, enabling the repair oxidative damage proteins and use sulfoxidation as regulatory switch. MetSO reductases catalyze stereospecific reduction MetSO. One mammalian reductases, MsrB3, has signal sequence for entry into endoplasmic reticulum (ER). In ER, MsrB3 expected encounter distinct redox environment compared with its paralogs in cytosol, nucleus, mitochondria. We sought determine location arrangement redox-active cysteines, which may couple activity other events ER. Results: determined human structure by using X-ray crystallography. revealed that disulfide bond near protein amino terminus distant space from active site. Nevertheless, biochemical assays showed these amino-terminal cysteines are oxidized site after reaction Innovation: This study reveals mechanism shuttle oxidizing equivalents primary toward enzyme surface, where they would be available further dithiol-disulfide exchange reactions. Conclusion: Conformational changes must occur during catalytic cycle transfer disulfide. accessibility this exposed help secretory pathway.