Recognition of UGA as a selenocysteine codon in Type I deiodinase requires sequences in the 3′ untranslated region

Berry, Marla J.; Banu, Laila Anjuman; Chen, Y Y; Mandel, Susan J.; Kieffer, J. David; Harney, John W.; Larsen, P. Reed

doi:10.1038/353273a0

Cited by 608 publications

(416 citation statements)

References 14 publications

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“…Selenocysteine is encoded by UGA, which normally acts as stop codon mediated by a multiprotein complex that includes Sec insertion sequence binding protein 2 (SECISBP2, also known as SBP2) (2). Failure of this mechanism can result in miscoding of the UGA codon to be read as a stop codon resulting in an untruncated inactive deiodinase protein.…”

Section: Deiodinase Deficiency Due To Inhibition Of Selenoprotein Synmentioning

confidence: 99%

“…The process of selenoprotein synthesis is complex because the codon for selenocysteine is UGA, which also serves as a translation STOP codon in about 50% of human mRNAs. Overcoming this stop codon function requires a series of proteins dedicated to the synthesis of the selenoproteins and a special tRNA upon which the selenocysteine molecule is synthesized (2,3) (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

“…2). Furthermore, eukaryotic selenoprotein mRNAs contain a hairpin loop structure in their 3' untranslated region, the SECIS element, which allows the ribosome to override the STOP codon function of the UGA (2,3).…”

Section: Introductionmentioning

confidence: 99%

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Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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Thyroxine (T4) is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

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Section: Deiodinase Deficiency Due To Inhibition Of Selenoprotein Synmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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“…Starting from these observations, the complex biosynthesis of selenoproteins was unraveled for bacteria in a transatlantic cooperation that remains inseparably associated with the names of Stadtman and Böck (Zinoni et al, 1986;Böck and Stadtman, 1988;Böck et al, 1991a,b). The attempts to understand eukaryotic selenoprotein biosynthesis has revealed homologies but also marked differences (Berry et al, 1991(Berry et al, , 1993, and has not yet yielded a satisfying comprehensive view.…”

Section: Introduction: Some Historical Landmarksmentioning

confidence: 99%

Selenium in Biology: Facts and Medical Perspectives

Köhrl¹,

Brigelius‐Flohé²,

Böck³

et al. 2000

Biological Chemistry

247

143

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Several decades after the discovery of selenium as an essential trace element in vertebrates approximately 20 eukaryotic and more than 15 prokaryotic selenoproteins containing the 21 st proteinogenic amino acid, selenocysteine, have been identified, partially characterized or cloned from several species. Many of these proteins are involved in redox reactions with selenocysteine acting as an essential component of the catalytic cycle. Enzyme activities have been assigned to the glutathione peroxidase family, to the thioredoxin reductases, which were recently identified as selenoproteins, to the iodothyronine deiodinases, which metabolize thyroid hormones, and to the selenophosphate synthetase 2, which is involved in selenoprotein biosynthesis. Prokaryotic selenoproteins catalyze redox reactions and formation of selenoethers in (stress-induced) metabolism and energy production of E. coli, of the clostridial cluster XI and of other prokaryotes. Apart from the specific and complex biosynthesis of selenocysteine, selenium also reversibly binds to proteins, is incorporated into selenomethionine in bacteria, yeast and higher plants, or posttranslationally modifies a catalytically essential cysteine residue of CO dehydrogenase. Expression of individual eukaryotic selenoproteins exhibits high tissue specificity, depends on selenium availability, in some cases is regulated by hormones, and if impaired contributes to several pathological conditions. Disturbance of selenoprotein expression or function is associated with deficiency syndromes (Keshan and Kashin-Beck disease), might contribute to tumorigenesis and atherosclerosis, is altered in several bacterial and viral infections, and leads to infertility in male rodents.

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“…The UGA recoding is strictly dependent on an RNA stem-loop structure, the Selenocysteine Insertion Sequence (SECIS), which is found in the 3' untranslated region of eukaryotic selenoprotein messages. 7 It also requires a specific elongation factor (EFSec), 8,9 a Sec-tRNA (Sec) that is unusual both in its structure and synthesis, 10,11 and SECIS-binding protein 2 (SBP2), an RNA-binding protein that mediates interactions of the selenocysteine insertion machinery with the selenoprotein mRNAs. 12,13 Several other proteins involved in tRNA synthesis, selenocysteine recycling and regulation of recoding efficiency have also been identified, reviewed in.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the UGA-recoding and SECIS-binding activities of SECIS-binding protein 2

2014

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Selenium, a micronutrient, is primarily incorporated into human physiology as selenocysteine (Sec). The 25 Seccontaining proteins in humans are known as selenoproteins. Their synthesis depends on the translational recoding of the UGA stop codon to allow Sec insertion. This requires a stem-loop structure in the 3' untranslated region of eukaryotic mRNAs known as the Selenocysteine Insertion Sequence (SECIS). The SECIS is recognized by SECIS-binding protein 2 (SBP2) and this RNA:protein interaction is essential for UGA recoding to occur. Genetic mutations cause SBP2 deficiency in humans, resulting in a broad set of symptoms due to differential effects on individual selenoproteins. Progress on understanding the different phenotypes requires developing robust tools to investigate SBP2 structure and function. In this study we demonstrate that SBP2 protein produced by in vitro translation discriminates among SECIS elements in a competitive UGA recoding assay and has a much higher specific activity than bacterially expressed protein. We also show that a purified recombinant protein encompassing amino acids 517-777 of SBP2 binds to SECIS elements with high affinity and selectivity. The affinity of the SBP2:SECIS interaction correlated with the ability of a SECIS to compete for UGA recoding activity in vitro. The identification of a 250 amino acid sequence that mediates specific, selective SECIS-binding will facilitate future structural studies of the SBP2:SECIS complex. Finally, we identify an evolutionarily conserved core cysteine signature in SBP2 sequences from the vertebrate lineage. Mutation of multiple, but not single, cysteines impaired SECIS-binding but did not affect protein localization in cells.

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Recognition of UGA as a selenocysteine codon in Type I deiodinase requires sequences in the 3′ untranslated region

Cited by 608 publications

References 14 publications

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Selenium in Biology: Facts and Medical Perspectives

Characterization of the UGA-recoding and SECIS-binding activities of SECIS-binding protein 2

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