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

Antioxidants & Redox Signaling
Gabriel JavittDeborah Fass

Abstract

Aims: The post-translational oxidation of methionine to methionine sulfoxide (MetSO) is a reversible process, enabling the repair of oxidative damage to proteins and the use of sulfoxidation as a regulatory switch. MetSO reductases catalyze the stereospecific reduction of MetSO. One of the mammalian MetSO 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 with its paralogs in the cytosol, nucleus, and mitochondria. 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 by 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 MetSO. 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...Continue Reading

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Citations

May 6, 2021·International Journal of Molecular Sciences·Tomasz PędzinskiBronislaw Marciniak

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Methods Mentioned

BETA
X-ray
nuclear magnetic resonance
NMR
electrophoresis
gel filtration
Circular dichroism

Software Mentioned

Molprobity
Coot
MassLynx
Phenix
MaxEnt
SignalP

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