MSRB3 Human

Methionine Sulfoxide Reductase B3 (MsrB3) is an enzyme that plays a crucial role in the repair of oxidatively damaged proteins. It specifically reduces methionine-R-sulfoxide back to methionine, thereby reversing the oxidative modification of methionine residues in proteins. This process is essential for maintaining protein function and cellular homeostasis, especially under conditions of oxidative stress.

MsrB3 exists in two splice variants that differ only in their N-terminal signal sequence. This sequence directs the protein to either the endoplasmic reticulum (ER) or mitochondria, indicating that MsrB3 functions in multiple cellular compartments . The enzyme contains an active site with a thiol group that is essential for its catalytic activity. Additionally, MsrB3 requires resolving cysteine residues for full enzymatic activity .

MsrB3 exhibits stereospecificity towards R-methionine sulfoxide, meaning it specifically targets and reduces this form of oxidized methionine. The reduction cycle of MsrB3 involves a three-step process:

1. Initial sulfenylation of the active site thiol.
2. Formation of an intrachain disulfide with a resolving thiol group.
3. Reduction of this disulfide by a thioredoxin-like protein to regenerate the active site thiol .

Interestingly, MsrB3 can also act as an oxidase, catalyzing the stereospecific formation of R-methionine sulfoxide. This dual functionality has important implications for the reversible modification of ER and mitochondrial proteins .

The oxidation of methionine residues in proteins can lead to alterations in protein function or trigger signaling events that result in changes in gene expression. MsrB3, by reversing this oxidation, helps maintain protein function and protect cells from oxidative damage . In mammalian cells, there are up to four known isoforms and two splice variants of methionine sulfoxide reductases, each differing in their cellular location and stereospecificity .

Deficiency in MsrB3 has been linked to autosomal recessive hearing loss in humans, specifically in the genetic condition known as DFNB74 . This highlights the enzyme’s importance in maintaining cellular function and its potential role in human health and disease.