Selenoproteins: molecular pathways and physiological roles

Abstract

Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

FIGURE 1.

The genetic code illustrating the dual function of the UGA codon and that Sec is the 21st amino acid that is encoded by UGA.

FIGURE 2.

Cloverleaf models of eukaryotic, archaeal, and bacterial tRNAs^[Ser]Sec.

FIGURE 3.

Mechanism of Sec biosynthesis in eukaryotes and the Sec machinery-based pathway for synthesis of Cys. The pathway for Sec biosynthesis in eukaryotes is shown, in which phosphoseryl-tRNA kinase (PSTK) provides the phosphorylated intermediate PSer-tRNA^[Ser]Sec serving as a substrate for SecS. Selenophosphate (H₂SePO₃⁻) generated by SPS2 from selenite and ATP is used as a donor of active Se for SecS (see top right portion of the figure for the final steps in Sec biosynthesis). The de novo synthesis of Cys using the Sec biosynthetic machinery is shown on the bottom right (see text for details).

FIGURE 4.

The PLP-dependent mechanism of eukaryotic SecS. A: amino group of O-phosphoseryl-tRNA^[Ser]Sec attacks the Schiff base (internal aldimine) between Lys284 and PLP to form an external aldimine. B: after the formation of the external aldimine, the side chain of Lys284 abstracts the Cα proton from phosphoserine. C: electron delocalization leads to β-elimination of phosphate and formation of dehydroalanyl-tRNA^[Ser]Sec. Free phosphate dissociates, whereas selenophosphate binds to the enzyme's active site. D: an unidentified base (-B) activates water that hydrolyzes selenophosphate. Se attacks the double bond of dehydroalanyl-tRNA^[Ser]Sec, and the second phosphate dissociates. Lys284 returns the proton to the Cα carbon leading to the formation of the selenocysteinyl moiety. E: Lys284 forms the Schiff base with PLP leading to the release of the oxidized form of Sec-tRNA^[Ser]Sec. F: the free amino group of Sec-tRNA^[Ser]Sec is protonated, and the active site of SecS is regenerated.

FIGURE 5.

Mechanism of Sec insertion in eukaryotes. The figure shows known factors that are required for Sec incorporation into proteins in response to the UGA codon. In addition, the factors that may influence the efficiency of the Sec insertion are shown, including ribosomal protein L30, a eukaryotic translation initiation factor eIF4a3, and nucleolin (see text for details).

FIGURE 6.

Structure of SECIS elements in eukaryotes (A), archaea (B), and bacteria (C). Consensus structures of SECIS elements with conserved nucleotides are shown. The indicated features and structural constraints represent the majority of SECIS elements found in selenoprotein mRNAs, but some additional exceptions may occur.

FIGURE 7.

Selenoprotein families. Selenoproteins that are found in vertebrates or single-cell eukaryotes are indicated by shaded boxes, whereas selenoproteins that occur in prokaryotic organisms are highlighted in red. The relative size of each selenoprotein is shown on the right, and the location of Sec residues is indicated by red lines.

FIGURE 8.

Redox reactions catalyzed Sec-containing oxidoreductases. First steps in the catalytic cycles are shown for thioredoxin reductase 1 (Trx1) (A), glutathione peroxidase 1 (GPx1) (B), and methionine sulfoxide reductase B1 (MsrB1) (C).

FIGURE 9.

Human selenoproteome. The relative length of selenoproteins and location of Sec within different proteins are shown on the right.

FIGURE 10.

Structures of mammalian selenoproteins. A: non-thioredoxin-fold selenoproteins. B: thioredoxin-fold proteins of the glutathione peroxidase (GPx) family. C: other (i.e., non-GPx) thioredoxin-fold selenoproteins. Helices are shown in dark gray, strands in black, and coils in light gray. For each protein, the catalytic Sec/Cys are shown as spacefills. Both mammalian TR1 and TR3 are homodimers, with one monomer shown in a ribbon representation, and the other monomer is shown as a backbone structure. The COOH terminus of TR3 (pdb code 1zdl) reported in the figure has been modeled based on the structure of human TR1 (pdb code 3ean). GPx1, GPx2, and GPx3 are natural homotetramers (only one monomer is shown). GPx1 has been crystallized with its Sec overoxidized.