Regulation of protein function by reversible methionine oxidation and the role of selenoprotein MsrB1

Abstract

Significance: Protein structure and function can be regulated via post-translational modifications by numerous enzymatic and nonenzymatic mechanisms. Regulation involving oxidation of sulfur-containing residues emerged as a key mechanism of redox control. Unraveling the participants and principles of such regulation is necessary for understanding the biological significance of redox control of cellular processes.

Recent advances: Reversible oxidation of methionine residues by monooxygenases of the Mical family and subsequent reduction of methionine sulfoxides by a selenocysteine-containing methionine sulfoxide reductase B1 (MsrB1) was found to control the assembly and disassembly of actin in mammals, and the Mical/MsrB pair similarly regulates actin in fruit flies. This finding has opened up new avenues for understanding the use of stereospecific methionine oxidation in regulating cellular processes and the roles of MsrB1 and Micals in regulation of actin dynamics.

Critical issues: So far, Micals have been the only known partners of MsrB1, and actin is the only target. It is important to identify additional substrates of Micals and characterize other Mical-like enzymes.

Future directions: Oxidation of methionine, reviewed here, is an emerging but not well-established mechanism. Studies suggest that methionine oxidation is a form of oxidative damage of proteins, a modification that alters protein structure or function, a tool in redox signaling, and a mechanism that controls protein function. Understanding the functional impact of reversible oxidation of methionine will require identification of targets, substrates, and regulators of Micals and Msrs. Linking the biological processes, in which these proteins participate, might also lead to insights into disease conditions, which involve regulation of actin by Micals and Msrs.

FIG. 1.

Met oxidation leads to the formation of two diastereomers of MetO. Met is converted to Met-S-SO or Met-R-SO by reactive oxygen species (ROS).

FIG. 2.

Localization and substrate specificity of Msrs. Both protein-based and free Met-S-SO forms are efficiently reduced by MsrA. MsrB mainly reduces protein-based Met-R-SO, whereas its activity toward free Met-R-SO is weak. Free Met-R-SO is reduced by fRMsr, but this enzyme occurs only in unicellular organisms. A single MsrA gene gives rise to nuclear, cytosolic, and mitochondrial forms of the protein. MsrB1 is located in the cytosol and nucleus, MsrB2 in mitochondria, and MsrB3 in the ER (humans also have an alternative form that localizes to mitochondria). MsrB1, methionine sulfoxide reductase B1.

FIG. 3.

Selenocysteine-containing MsrB1. Mammalian MsrB1 is a selenoprotein that contains selenocysteine (Sec) in place of the catalytic Cys in other MsrBs. As true for other selenoprotein genes, the MsrB1 gene has an SECIS element in the 3′-untranslated region that supports co-translational Sec insertion at the in-frame UGA codon with the help of Sec-tRNA, SECIS-binding protein SBP2, and Sec-specific elongation factor EFSec.

FIG. 4.

Functions of Msrs. Three groups of Msr functions are known, including (A) protection against oxidative stress by removing ROS via Met oxidation and MetO reduction, (B) repair of protein function in situations when target proteins lose their functions on Met oxidation, and (C) regulation of protein function by reversible Met oxidation and MetO reduction.

FIG. 5.

Historical perspective on proteins identified as substrates of Msrs. Functions of these proteins are regulated by reversible Met oxidation. See text for details.

FIG. 6.

Co-regulation of actin assembly by Micals and MsrB1. Micals oxidize two conserved Mets in actin to Met-R-SO, leading to actin depolymerization (forming G-actin), whereas MsrB1 reduces these Met-R-SOs to Met that promotes actin repolymerization (forming F-actin).