6qa0 | pdb_00006qa0
MSRB3 - AA 1-137
Structural highlights
DiseaseMSRB3_HUMAN Autosomal recessive non-syndromic sensorineural deafness type DFNB. The disease is caused by mutations affecting the gene represented in this entry. A nonsense mutation affecting exclusively mitochondrial isoform 2 is sufficient to produce hearing loss. FunctionMSRB3_HUMAN Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine. Isoform 2 is essential for hearing.[1] [2] Publication Abstract from PubMedINTRODUCTION: 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. Structure and Electron-transfer Pathway of the Human Methionine Sulfoxide Reductase MsrB3.,Javitt G, Cao Z, Resnick E, Gabizon R, Bulleid N, Fass D Antioxid Redox Signal. 2020 Jun 10. doi: 10.1089/ars.2020.8037. PMID:32517586[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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