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Keywords:

  • selenoprotein biosynthesis;
  • selenium;
  • selenoprotein

Abstract

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

Selenium is an essential micronutrient that has been linked to various aspects of human health. Selenium exerts its biological activity through the incorporation of the amino acid, selenocysteine (Sec), into a unique class of proteins termed selenoproteins. Sec incorporation occurs cotranslationally at UGA codons in archaea, prokaryotes, and eukaryotes. UGA codons specify Sec coding rather than termination by the presence of specific secondary structures in mRNAs termed selenocysteine insertion (SECIS) elements, and trans-acting factors that associate with SECIS elements. Herein, we discuss the various proteins known to function in eukaryotic selenoprotein biosynthesis, including several players whose roles have only been elucidated very recently. © 2008 IUBMB IUBMB Life, 60(4): 232–235, 2008


PHOSPHOSERYL-tRNA[SER]SEC KINASE

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

In 1989 selenocysteine (Sec) was identified as the 21st amino acid, and unlike other amino acids, it is synthesized on its transfer RNA, tRNA[Ser]Sec (1, 2). tRNA[Ser]Sec is initially aminoacylated with serine, then phosphorylated to form phosphoseryl-tRNA[Ser]Sec, and converted to selenocysteyl-tRNA[Ser]Sec (3, 4). In 1970, a minor species of seryl-tRNA was discovered in rooster liver and was shown to be converted to phosphoseryl-tRNA by a kinase (5). The seryl-tRNA was subsequently demonstrated to associate with UGA codons (6) and decode UGA in vitro (7, 8), and was later identified as selenocysteyl-tRNA[Ser]Sec (1, 2). For years, identification of the phosphoseryl kinase remained elusive; however, recent in silico analyses of the archeal and eukaryotic genomes for novel kinase-like genes that are present within genomes containing the Sec incorporation genes revealed a candidate, phosphoseryl-tRNA[Ser]Sec kinase gene. Phosphoseryl- tRNA[Ser]Sec kinase was subsequently cloned and characterized as a protein that phosphorylates the seryl moiety on seryl-tRNA[Ser]Sec in the presence of ATP and Mg2+ (9).

SEC SYNTHASE

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

Sec synthesis was initially established in E. coli in the early 1990s. The process occurs on the seryl-tRNA[Ser]Sec molecule and is catalyzed by the bacterial enzyme, Sec synthase (SecS), encoded by the SelA gene (10, 11). SecS, a pyridoxal phosphate-dependent enzyme, esterifies the serine moiety of seryl-tRNA[Ser]Sec, forming an aminoacrylyl intermediate which is then exchanged with selenol. Recent studies have identified soluble liver antigen, a 48-kDa protein tRNA[Ser]Sec binding protein, as the eukaryotic SecS (3, 4, 12). Eukaryotic SecS is also a member of the pyridoxal phosphate- dependent transferase superfamily (13) and associates with the supramolecular complex mediating Sec incorporation into selenoproteins (14). SecS dephosphorylates O-phosphoseryl tRNA[Ser]Sec and transfers monoselenophosphate onto the tRNA to form selenocysteyl-tRNA[Ser]Sec (3, 4).

SECP43

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

SecP43 was identified in a degenerate PCR screen for RNA binding proteins, and shown to bind to selenocysteyl-tRNA[Ser]Sec (15). RNA interference studies targeting SecP43 demonstrated that the protein is required for methylation of the 2′-hydroxylribosyl moiety in the wobble position of the selenocysteyl-tRNA[Ser]Sec and enhances selenoprotein expression. Analysis of the subcellular localization of SecP43 suggests that it may regulate shuttling of the SecS-selenocysteyl-tRNA[Ser]Sec complex between the nucleus and cytoplasm (14, 16).

SELENOPHOSPHATE SYNTHETASE

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

Monoselenophosphate is the active form of selenium, which is transferred to the seryl-tRNA[Ser]Sec to generate selenocysteyl-tRNA[Ser]Sec in prokaryotes (17) and eukaryotes (3, 4). Bacterial selenophosphate synthetase, encoded by the SelD gene, generates monoselenophosphate from selenide and ATP (17). The eukaryotic SelD homologues, selenophosphate synthetase 1 (SPS1) and selenophosphate synthetase 2 (SPS2), were first identified in mammals and implicated as essential components in selenoprotein synthesis (18–22). Interestingly, SPS2 is a selenoprotein and thereby may autoregulate its own production along with the production of other selenoproteins (20). It has recently been reported that SPS2 synthesizes selenophosphate in vitro whereas SPS1 does not (3, 4). SPS1 has been speculated to play a role in Sec recycling and selenium salvage (23). Subsequent in vivo knockdown studies of the two proteins in NIH3T3 cells has revealed that SPS2 serves to generate the active selenium donor for Sec synthesis whereas SPS1 does not (3, 4). Further studies are necessary to elucidate the roles of SPS1 and SPS2 in selenoprotein synthesis.

EFSEC

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

Sec decoding employs a selenocysteyl-tRNA[Ser]Sec specific elongation factor in both prokaryotes (SELB or EFsec) and eukaryotes (eEFSec). The prokaryotic factor is a GTP-dependent RNA binding protein consisting of an N-terminal elongation factor domain specific to selenocysteyl-tRNA[Ser]Sec, and a C-terminal selenocysteine insertion (SECIS) binding domain (24–26). EFsec delivers selenocysteyl-tRNA[Ser]Sec to the ribosomal A site for Sec incorporation into the nascent protein (25), dissociates from the ribosome and the SECIS element, and reassembles with selenocysteyl-tRNA[Ser]Sec for the subsequent round of Sec incorporation (27). In silico analysis of eukaryotic genomes resulted in identification of the murine Sec elongation factor, eEFSec (28, 29). Like its prokaryotic counterpart, eEFsec binds to selenocysteyl-tRNA[Ser]Sec; however, it does not associate directly with SECIS elements (28, 29). Instead, eEFsec associates with SECIS binding protein 2 (SBP2) in the presence of selenocysteyl-tRNA[Ser]Sec, thereby forming the Sec decoding apparatus (28, 30).

SECIS BINDING PROTEIN 2

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

SBP2 was discovered in rat testicular extracts by RNA affinity chromatography using SECIS elements as RNA ligand (31). SBP2 stimulates Sec incorporation in vivo and in vitro (31–33) by associating with SECIS elements and recruiting the eEFSec-selenocysteyl-tRNA[Ser]Sec complex to the ribosome (28). SBP2 binds to the large ribosomal subunit and a conserved internal loop domain within the core of the SECIS (33, 34). SBP2 contains an RNA binding domain common to the ribosomal binding proteins L30 and eRF1, and the SUP1 protein (32), a suppressor of translational termination in yeast (35). Mutagenesis of this conserved RNA binding domain abolishes SECIS binding but not ribosomal binding (33). Recent reports have identified naturally occurring mutations affecting SBP2-SECIS binding and Sec decoding capacity. Missense mutations in the RNA binding domain of SBP2 identified in patients with abnormal thyroid hormone metabolism (36) have been shown to confer diminished SECIS binding affinity in vitro (37) and in vivo (38). A homozygous point mutation within the SBP2 binding domain of the SelN SECIS was recognized in patients with rigid spine muscular dystrophy. The mutation decreases SBP2 binding capacity and downregulates SelN expression (38). We have recently demonstrated that SBP2 binding affinity differs between selenoprotein mRNAs and is a major determinant in differential selenoprotein mRNA translation and sensitivity to nonsense-mediated decay (38). Subcellular localization studies of the protein suggest that SBP2 undergoes nucleocytoplasmic shuttling and complexes with the Sec incorporation machinery in the nucleus, thereby allowing selenoprotein mRNAs to circumvent nonsense-mediated decay (40). Furthermore, the redox state of SBP2 regulates its subcellular localization and Sec decoding function. Oxidative stress induces nuclear sequestration of SBP2, and possibly its associated mRNAs, and results in downregulation of selenoprotein synthesis (41).

L30

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

The ribosomal protein L30 interacts with SECIS elements at a site overlapping the SBP2 binding site. L30 promotes Sec decoding, and competes with SBP2 for SECIS binding under conditions of high magnesium (42). Magnesium is thought to induce a kink-turn in the SECIS RNA structure and enhance L30-SECIS binding activity while attenuating SBP2's SECIS interaction (42). During UGA recoding, L30 has been proposed to displace SBP2 from the selenoprotein mRNA by inducing a conformational change in the SECIS element and tethering the Sec decoding apparatus to the large ribosomal subunit. Disassociation of SBP2 from the SECIS putatively releases selenocysteyl-tRNA into the ribosomal A site and stimulates eEFSec GTP hydrolysis, thereby recycling these factors for the subsequent round of Sec decoding (42).

NUCLEOLIN

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

In 2000, nucleolin, a protein best known for its involvement in ribosome synthesis, was identified as a selenoprotein mRNA-binding protein in a cDNA library screen utilizing radiolabeled glutathione peroxidase mRNA as a probe. The nucleolin-SECIS interaction was subsequently confirmed by RNA electrophoretic mobility shift assays (43). We have recently reported that unlike SBP2, which exhibits strong preferential binding to some selenoprotein mRNAs over others, nucleolin exhibits minimal differences in selenoprotein mRNA binding, and thus is unlikely to contribute to the hierarchy of selenoprotein synthesis but may play a role in Sec translation or transport (38).

SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES

We propose the mechanism shown in Fig. 1 for Sec biosynthesis and insertion into a nascent selenoprotein. Additional factors may exist in the process and their discovery should provide a more inclusive mechanistic insight into the synthesis of these unique proteins.

thumbnail image

Figure 1. The hypothetical mechanism of selenocysteine biosynthesis and incorporation into selenoproteins.

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REFERENCES

  1. Top of page
  2. Abstract
  3. PHOSPHOSERYL-tRNA[SER]SEC KINASE
  4. SEC SYNTHASE
  5. SECP43
  6. SELENOPHOSPHATE SYNTHETASE
  7. EFSEC
  8. SECIS BINDING PROTEIN 2
  9. L30
  10. NUCLEOLIN
  11. SEC BIOSYNTHESIS AND ITS INSERTION INTO PROTEIN
  12. REFERENCES
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