Abstract
ABSTRACTMethionine sulfoxide reductase A (MsrA) is an antioxidant enzyme found in all domains of life that catalyzes the reduction of methionine-S-sulfoxide (MSO) to methionine in proteins and free amino acids. We demonstrate that archaeal MsrA has a ubiquitin-like (Ubl) protein modification activity that is distinct from its stereospecific reduction of MSO residues. MsrA catalyzes this Ubl modification activity, with the Ubl-activating E1 UbaA, in the presence of the mild oxidant dimethyl sulfoxide (DMSO) and in the absence of reductant. In contrast, the MSO reductase activity of MsrA is inhibited by DMSO and requires reductant. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis reveals that MsrA-dependent Ubl conjugates are associated with DNA replication, protein remodeling, and oxidative stress and include the Ubl-modified MsrA, Orc3 (Orc1/Cdc6), and Cdc48d (Cdc48/p97 AAA+ ATPase). Overall, we found archaeal MsrA to have opposing MSO reductase and Ubl modifying activities that are associated with oxidative stress responses and controlled by exposure to mild oxidant.
Highlights
Methionine sulfoxide reductase A (MsrA) is an antioxidant enzyme found in all domains of life that catalyzes the reduction of methionine-S-sulfoxide (MSO) to methionine in proteins and free amino acids
MsrA/B are covalently linked to SAMP1 in Hfx. volcanii cells treated with the mild oxidant dimethyl sulfoxide (DMSO) [19]
The ⌬msrA mutant was found to be severely impaired in the level of SAMP1/2/3 conjugates that formed in the presence of DMSO, compared to the parent strain and the ⌬msrB mutant (Fig. 1, lane 5 versus lanes 4 and 6 [SAMP1], lane 11 versus lanes 10 and 12 [SAMP2], and lane 19 versus lanes 18 and 20 [SAMP3])
Summary
Methionine sulfoxide reductase A (MsrA) is an antioxidant enzyme found in all domains of life that catalyzes the reduction of methionine-S-sulfoxide (MSO) to methionine in proteins and free amino acids. MsrA/B are covalently linked to SAMP1 in Hfx. volcanii cells treated with the mild oxidant DMSO [19].
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