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Selenoproteins: Biosynthesis and Functions

Selenoproteins: Biosynthesis and Functions. Vadim N. Gladyshev. Selenium is essential for human health Selenium deficiency may cause. Increased risk of prostate, colon and lung cancers Increased risk of AIDS in HIV-infected individuals Male reproduction problems

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Selenoproteins: Biosynthesis and Functions

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  1. Selenoproteins: Biosynthesis and Functions Vadim N. Gladyshev

  2. Selenium is essential for human healthSelenium deficiency may cause • Increased risk of prostate, colon and lung cancers • Increased risk of AIDS in HIV-infected individuals • Male reproduction problems • Increased risk of viral infection • Keshan, Kashin-Beck diseases

  3. O CH2NHCH3 HN Se N HO O H Se CH2 OH HO + - H3N COO C H Biological forms of selenium Other forms: selenomethionine, Se cofactor • 5-methylaminomethyl-2-selenouridine (mnm5Se2U, SeU) Selenoproteins Some tRNAs

  4. Se is present in proteins in the form of 21st amino acid - selenocysteine • Selenocysteine is encoded by UGA; UGA is also a stop signal • mRNA structure, selenocysteine insertion sequence (SECIS) element, is essential for insertion of selenocysteine

  5. 34 H Se Se CH2 + - H3N COO C 78.96 H Selenium (Se) • Eukaryotes: >30 families • - Deiodinase: DI, DII and DIII • - Glutathione peroxidase:GPx1-4, GPx6 • - Thioredoxin reductase: TR1, TGR, TR3 • - MsrB1 • - SPS2 • - MsrA • - Protein disulfide isomerase • - SelH, SelI, SelJ, SelK, SelL, SelN, SelP, SelS, SelW, etc. • Prokaryotes: >60 families • - Formate dehydrogenase FdhA • - SelD • - FrhA and FrhD • - GrdA and GrdB • - Peroxiredoxin • - Thioredoxin • - Glutaredoxin • - Proline reductase • - Rhodanase-related protein • - Arsenate reductase • - HesB-like • - GST-like • - GPx-like, SelW-like, DsbA-like • - Various Prx/Trx/Grx-like protein families Selenoprotein Selenocysteine (21st amino acid)

  6. A general model of Se metabolism in bacteria Sulfate/Selenate (selenite?) Selenite ? Sulfide/Selenide Se-containing cofactor O-acetylserine [Se-] Seryl-tRNA[Ser]Sec Cysteine/Selenocysteine pool SelD Selenophosphate SelA S/Se-Cystationine S/Se-Cys-tRNACys mnm5Se2U mnm5s2U YbbB Selenocysteyl-tRNA[Ser]Sec S/Se-Methionine SelB Selenoprotein S/Se-Met-tRNAMet Selenylated proteins

  7. Se H Se- OH HO P O- Sec SelB Sec-tRNA[Ser]Sec Sec biosynthesis and insertion in bacteria SelD (Selenide) (Selenophosphate) Ser SerS SelA Ser SECIS tRNA[Ser]Sec Ser-tRNA[Ser]Sec UAA UAG UGA UGA (Sec) AUG

  8. H Se- Sec biosynthesis and insertion in eukaryotes SPS2 3’ Selenophosphate SBP2 P Ser Sec Ser Ser eEFSec SECIS SerS PSTK SecS Sec-tRNA[Ser]Sec tRNA[Ser]Sec Ser-tRNA[Ser]Sec O-Phosphoseryl-tRNA[Ser]Sec UAA UAG UGA UGA (Sec) AUG 5’

  9. To understand selenium biology and its role in human health, information on identities, locations and functions of all selenoproteins is required Selenoprotein 1 Selenoprotein 2 Selenoprotein 3 Selenoprotein 4 Selenoprotein 5 Cancer prevention Male reproduction Aging Immune function Other

  10. Searches for selenoprotein genes Selenoprotein SECIS Initiation of translation Selenocysteine UGA STOP AUG AAAAAAA 3’ 5’ UAA UAG UGA Cys-containing protein Initiation of translation STOP AUG AAAAAAA 3’ 5’ UAA UAG UGA Cysteine UGC UGU

  11. SECISearch on-line http://genomics.unl.edu/SECISearch.html

  12. Record holders Selenoproteomes Families Eukaryotes: 0-57 (Aureococcus) 29 Bacteria: 0-57 (worm symbiont) 27 Archaea: 0-9 (M. maripaludis) 7 Viruses: 0-1 (fowlpox virus) 1 Model organisms Organism Selenoproteins Mouse, rat 24 Zebrafish 37 Drosophila 3 C. elegans 1 S. cerevisiae, Arabidopsis 0

  13. Selenoprotein functions in mammals Peroxide removal Glutathione peroxidase Phospholipid hydroperoxide glutathione peroxidase Thyroid hormone metabolism Iodothyronine deiodinase Reduction of thioredoxin Thioredoxin reductase Protein repair Methionine sulfoxide reductase Reduction of ryanodine receptor Selenoprotein N Retrotranslocation of proteins from the ER to cytosol Selenoprotein S Generation of Se donor compound Selenophosphate synthetase Transport of Se from liver to other organs Selenoprotein P

  14. Selenocysteine versus Cysteine Cysteine Selenocysteine UGU, UGC-codons UGA codon pKa = 8.3 pKa = 5.2 S- S Se- S S S Sec serves redox function!

  15. Kryukov et al., Science 300, 1439 (2003)

  16. Selenoproteins in the endoplasmic reticulum

  17. SelS – retrotranslocation of misfolded proteins from the ER to cytosol

  18. Selenoproteins in arthropods

  19. Selenoproteins: a subset of thiol oxidoreductases Metabolic processes ROS detoxification Signal transduction Thiol Redoxome – a set of thiol oxidoreductases in an organism Transcription control Protein degradation Protein modification Oxidative folding

  20. High-throughout identification of catalytic redox-active cysteine residues Fomenko et al., Science 315, 387-389 (2007)

  21. Essentially all known thiol oxidoreductases could be detected by the Sec/Cys approach Thioredoxin Methionine-S-sulfoxide reductase Glutaredoxin Methionine-R-sulfoxide reductase AhpD Glutathione peroxidase DsbA Peroxiredoxin Protein disulfide isomerase Arsenate reductase Thioredoxin reductase Ohr (OsmC)

  22. Functions of Cys in proteins 1. Redox catalysis (e.g., thiol oxidoreductases) 2. Regulatory cysteines (e.g., kinases, phosphatases) 3. Structural disulfides (e.g., secretory proteins) 4. Metal-coordinating cysteines (e.g., zinc fingers) 5. Non-redox catalysis (e.g., certain proteases) 6. Sites of posttranslational modifications (e.g., membrane targeting) 7. Other functions

  23. Schizosaccharomyces Saccharomyces Caenorhabditis Homo Dictyostelium Arabidopsis Zea Tetrahymena Paramecium Euplotes Oxytricha Toxoplasma Plasmodium Cryptosporidium Trypanosoma Leishmania Giardia Euplotes crassus www.microscopyu.com Genetic code: UGA Cys UAA, UAG Stop

  24. Location of UGA encoded residues Glutathione peroxidase 1 Glutathione peroxidase 2 Thioredoxin reductase 1 Thioredoxin reductase 2 Selenoprotein W1 Selenoprotein W2 Selenoprotein W3 Pfam09409 protein E. crassus HEK 293 O. tauri D. salina 98 62 TR1 49 38 28 GPx1 GPx4 17 14 6 3 eGPx1 eGPx2 eTR1 eTR2 eSelW1 eSelW2 eSelW3 Pfam09409 E. crassus selenoproteome

  25. Sec is inserted only at codon 497 full eTR1 eTR1-68 eTR1-420 eTR1-497 control 98 GFP- eTR1 62 49 38 28 17 14 6 3 1 2 3 4 5

  26. C Accessibility of the SECIS element determines which amino acid is inserted at UGA codon mRNA SECIS element unavailable: Cys insertion SECIS UGA SECIS mRNA SECIS element available: Sec insertion U UGA

  27. Not known in mammals 1. Se import and export (SelP, selenite, selenosugar) 2. Functions of glutathione peroxidases 3 and 6, thioredoxin-glutathione reductase, selenoproteins S and N 3. Functions of selenoproteins H, I, K, M, O, T, W, V and Sep15 4. Functions of SPS1, SBP1, Sec lyase 5. Why is Sec used in biology

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