Functions and evolution of selenoprotein methionine sulfoxide reductases

Abstract

Methionine sulfoxide reductases (Msrs) are thiol-dependent enzymes which catalyze conversion of methionine sulfoxide to methionine. Three Msr families, MsrA, MsrB, and fRMsr, are known. MsrA and MsrB are responsible for the reduction of methionine-S-sulfoxide and methionine-R-sulfoxide residues in proteins, respectively, whereas fRMsr reduces free methionine-R-sulfoxide. Besides acting on proteins, MsrA can additionally reduce free methionine-S-sulfoxide. Some MsrAs and MsrBs evolved to utilize catalytic selenocysteine. This includes MsrB1, which is a major MsrB in cytosol and nucleus in mammalian cells. Specialized machinery is used for insertion of selenocysteine into MsrB1 and other selenoproteins at in-frame UGA codons. Selenocysteine offers catalytic advantage to the protein repair function of Msrs, but also makes these proteins dependent on the supply of selenium and requires adjustments in their strategies for regeneration of active enzymes. Msrs have roles in protecting cellular proteins from oxidative stress and through this function they may regulate lifespan in several model organisms.

Figure 1

Reversible generation and reduction of methionine sulfoxide. MsrA can reduce both free and protein-based methionine-S-sulfoxide. MsrB mainly reduces protein-based methionine-R-sulfoxide and its activity towards free methionine-R-sulfoxide is very weak. fRMsr can only reduce free methionine-R-sulfoxide.

Figure 2

Localization of Msrs in mammals. MsrA and MsrB1 are located in the nucleus and cytosol. MsrA, MsrB2, and MsrB3B are targeted to mitochondria by their mitochondrial targeting signals. Human MsrB3A is located in the ER and has N-terminal ER targeting and C-terminal retention signals, whereas human MsrB3B is a mitochondrial protein. Mouse MsrB3 is located in the ER. There are alternatively spliced variants of MsrA, which are not shown in the figure and localize to cytosol and nucleus, or to mitochondria.

Figure 3

Catalytic mechanisms of Msrs. Catalytic cysteine (CC), resolving cysteine (RC), and/or third cysteine (TC) take part in the catalysis by (A) MsrA, (B) fRMsr, (C) MsrB1, and (D) MsrB2 and MsrB3. MsrA and fRMsr have three conserved cysteines. MsrB1 has one conserved cysteine and one conserved selenocysteine. MsrB2 and MsrB3 have only one redox cysteine and its intermediate sulfenic acid may be directly reduced by thioredoxin or certain compounds.

Figure 4

Selenoprotein biosynthesis. Selenocysteine is inserted into protein at UGA codons with the help of various factors that form the selenocysteine insertion machinery as shown in the figure. Sec-tRNA^Sec, a tRNA specific for selenocysteine; SBP2, SECIS binding protein 2; EFSec, elongation factor specific for Sec-tRNA.

Figure 5

Methionine and methionine sulfoxide metabolism in mammals. Protein synthesis, methionine cycle and transsulfuration pathways represent the major uses of free methionine.