PROSITE documentation PDOC51790

Methionine-R-sulfoxide reductase (MsrB) domain profile

Methionine (Met) residues in either free or protein-based forms are a major target of reactive oxygen species (ROS)-induced oxidation and are converted to S and R epimers of methionine sulfoxide (MetSO). The oxidative modification of Met leads to changes in structure and function of many proteins. Living organisms evolved methionine sulfoxide reductase (MSR), which reverses MetSO back to Met to counteract Met oxidation by ROS. The two major types of MSR are MsrA and MsrB, which are specific for methionine S-sulfoxide (Met-S-SO) and methionine R-sulfoxide (Met-R-SO), respectively. These two classes of enzymes display neither sequence nor structural homology, but share a 'mirrored catalytic mechanism'. Hence, this represents an compelling case of convergent evolution. Functions of these proteins include repair of oxidatively damaged proteins, regulation of protein function and elimination of oxidants through reversible formation of methionine sulfoxides. Most organisms contain MsrA and MsrB typically as separate enzymes. However, MsrA and MsrB exist as domains in a single fused protein (MsrAB) in some bacteria such as Streptococcus pneumonia, Neisseria gonorrhoea and Haemophilus influenza. MsrB proteins have been identified and characterized in various organisms including bacteria, yeast, fruit fly, and mammals [1,2,3,4,5,6].

The MsrB core domain is composed of two antiparallel β-sheets generated by strands β1, β2 and strands β9 and β3-β7, respectively (see <PDB:1L1D>). Alignment of MSRB sequences reveals only a single Cys that is conserved in all family members. The Cys is located in the C-terminal part of the protein and is the catalytic residue that directly attacks MetSO. The MsrB domain activates the cysteine or selenocysteine nucleophile through a unique Cys-Arg-Asp/Glu catalytic triad. The collapse of the reaction intermediate most likely results in the formation of a sulfenic or seleneic acid moiety. Regeneration of the active site occurs through a series of thiol-disulfide exchange steps involving another active site Cys residue and thioredoxin. The first step in the catalytic cycle (reductase step) leads to the formation of a sulphenic acid intermediate on the catalytic Cys with the concomitant release of reduced Met. Immediately, an intramolecular disulphide bond is formed via the attack of a second Cys (recycling Cys) on the sulphenic acid intermediate and the release of a water molecule. Finally, this disulphide bond is reduced via an inter-molecular thiol-disulphide exchange by thioredoxin to regenerate the active-site Cys-thiol function. The second Cys that is involved in the recycling of the active site ('recycling Cys') is not universally conserved. Many MSRB sequences carry four additional conserved Cys residues that are organized in two CXXC motifs, which co-ordinate a zinc ion required for the enzymatic activity [1,4,5].

The profile we developed covers the entire MsrB domain.