Abstract:
Selenoprotein R (SelR) is a mammalian selenocysteine-containing
protein with no known function. Here we report that cysteine
homologs of SelR are present in all organisms except certain parasites
and hyperthermophiles, and this pattern of occurrence closely
matches that of only one protein, peptide methionine sulfoxide
reductase (MsrA). Moreover, in several genomes, SelR and MsrA
genes are fused or clustered, and their expression patterns suggest a
role of both proteins in protection against oxidative stress. Consistent
with these computational screens, growth of Saccharomyces cerevisiae
SelR and MsrA mutant strains was inhibited, and the strain
lacking both genes could not grow, in the presence of H2O2 and
methionine sulfoxide. We found that the cysteine mutant of mouse
SelR, as well as the Drosophila SelR homolog, contained zinc and
reduced methionine-R-sulfoxide, but not methionine-S-sulfoxide, in
in vitro assays, a function that is both distinct and complementary to
the stereo-specific activity of MsrA. These findings identify a function
of the conserved SelR enzyme family, define a pathway of methionine
sulfoxide reduction, reveal a case of convergent evolution of
similar function in structurally distinct enzymes, and suggest a
previously uncharacterized redox regulatory role of selenium in
mammals.
