title: Regulation of Selenocysteine Content of Human Selenoprotein P by Dietary Selenium and Insertion of Cysteine in Place of Selenocysteine.
abstract: Selenoproteins are a unique group of proteins that contain selenium in the form of selenocysteine (Sec) co-translationally inserted in response to a UGA codon with the help of cis- and trans-acting factors. Mammalian selenoproteins contain single Sec residues, with the exception of selenoprotein P (SelP) that has 7-15 Sec residues depending on species. Assessing an individual's selenium status is important under various pathological conditions, which requires a reliable selenium biomarker. Due to a key role in organismal selenium homeostasis, high Sec content, regulation by dietary selenium, and availability of robust assays in human plasma, SelP has emerged as a major biomarker of selenium status. Here, we found that Cys is present in various Sec positions in human SelP. Treatment of cells expressing SelP with thiophosphate, an analog of the selenium donor for Sec synthesis, led to a nearly complete replacement of Sec with Cys, whereas supplementation of cells with selenium supported Sec insertion. SelP isolated directly from human plasma had up to 8% Cys inserted in place of Sec, depending on the Sec position. These findings suggest that a change in selenium status may be reflected in both SelP concentration and its Sec content, and that availability of the SelP-derived selenium for selenoprotein synthesis may be overestimated under conditions of low selenium status due to replacement of Sec with Cys.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Turanov
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Everley
authors.affiliation: Institute for Experimental Endocrinology, Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hybsier
authors.affiliation: Institute for Experimental Endocrinology, Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kostja
authors.initials: K
authors.lastname: Renko
authors.affiliation: Institute for Experimental Endocrinology, Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America.
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003545:Cysteine; D004032:Diet; D056945:Hep G2 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010710:Phosphates / Q000494:pharmacology; D020887:Selenious Acid / Q000494:pharmacology; D012643:Selenium / Q000494:pharmacology*; D017279:Selenocysteine; D051149:Selenoprotein P / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D010710:Phosphates; D051149:Selenoprotein P; D017279:Selenocysteine; D020887:Selenious Acid; D012643:Selenium; D003545:Cysteine; C035638:thiophosphoric acid