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Review
. 2009 Jul 29;422(1):11-22.
doi: 10.1042/BJ20090219.

Regulation and function of selenoproteins in human disease

Frederick P Bellinger  1 , Arjun V Raman, Mariclair A Reeves, Marla J Berry
Affiliations
Review

Regulation and function of selenoproteins in human disease

Frederick P Bellinger et al. Biochem J. .

Abstract

Selenoproteins are proteins containing selenium in the form of the 21st amino acid, selenocysteine. Members of this protein family have many diverse functions, but their synthesis is dependent on a common set of cofactors and on dietary selenium. Although the functions of many selenoproteins are unknown, several disorders involving changes in selenoprotein structure, activity or expression have been reported. Selenium deficiency and mutations or polymorphisms in selenoprotein genes and synthesis cofactors are implicated in a variety of diseases, including muscle and cardiovascular disorders, immune dysfunction, cancer, neurological disorders and endocrine function. Members of this unusual family of proteins have roles in a variety of cell processes and diseases.

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Figures

Figure 1
Figure 1. Selenoprotein involvement in cellular antioxidant systems
Selenoproteins (highlighted in blue) have critical roles in both the GSH-dependent and TRX-dependent antioxidant systems. GPXs catalyse the breakdown of peroxides into water. SelH increases expression of the GSH-synthesis enzyme GCS (γ-glutamylcysteine synthetase). TRXRs reduce oxidized TRXs. Certain selenoproteins, such as SelR and SelP, use TRX as an electron donor to form redox couples for detoxification of oxidized proteins and lipids. Protein/Lipid could be protein phosphatases, protein kinases, transcription factors or membrane protein/lipids. GSR, glutathione reductase; SOD, superoxide dismutase. An animated version of this Figure can be seen at http://www.BiochemJ.org/bj/422/0011/bj4220011add.htm.
Figure 2
Figure 2. Machinery involved in synthesis of selenoproteins
Selenium phosphorylated by SPS1 is used to synthesize Sec from serine directly on the tRNASec by the enzyme Sec synthetase. tRNASec is transported to the nucleus with many cofactors bound. The protein SBP2 binds to the SECIS element in the 3′-UTR of selenoprotein mRNAs, and recruits the tRNASec complex along with bound cofactors. The assembled complex is transported from the nucleus for translation to protein. HSP90, heat-shock protein 90.
Figure 3
Figure 3. SelN and ryanodine receptors
(A) SelN interacts with ryanodine receptors to control release of calcium from intracellular stores. (B) Mutations in both SelN and ryanodine receptors can cause multiminicore disease, a form of muscular dystrophy. IP3, inositol trisphosphate; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; SR, sarcoplasmic reticulum.
Figure 4
Figure 4. Role of SelS in removal of misfolded proteins from ER
(A) SelS is an ER membrane protein that interacts with the ER membrane protein derlin and the cytosolic ATPase p97 to transport misfolded proteins out of the ER. Once in the cytosol, the protein is tagged with ubiquitin via the E3 ubiquitin ligase and shuttled to the cell proteasome. (B) Promoter SelS polymorphisms can down-regulate expression of SelS, causing a build up of misfolded proteins in the ER. Stress to the ER can induce NF-κB, which can up-regulate inflammatory cytokines, and can also lead to apoptosis.
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