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. 2020 Sep 1;33(7):481-497.
doi: 10.1089/ars.2020.8097. Epub 2020 May 11.

Human Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency

Erik Schoenmakers  1 , Krishna Chatterjee  1
Affiliations

Human Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency

Erik Schoenmakers et al. Antioxid Redox Signal. .

Abstract

Significance: Generalized selenoprotein deficiency has been associated with mutations in SECISBP2, SEPSECS, and TRU-TCA1-1, 3 factors that are crucial for incorporation of the amino acid selenocysteine (Sec) into at least 25 human selenoproteins. SECISBP2 and TRU-TCA1-1 defects are characterized by a multisystem phenotype due to deficiencies of antioxidant and tissue-specific selenoproteins, together with abnormal thyroid hormone levels reflecting impaired hormone metabolism by deiodinase selenoenzymes. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Recent Advances: The recent identification of individuals with defects in genes encoding components of the selenocysteine insertion pathway has delineated complex and multisystem disorders, reflecting a lack of selenoproteins in specific tissues, oxidative damage due to lack of oxidoreductase-active selenoproteins and other pathways whose nature is unclear. Critical Issues: Abnormal thyroid hormone metabolism in patients can be corrected by triiodothyronine (T3) treatment. No specific therapies for other phenotypes (muscular dystrophy, male infertility, hearing loss, neurodegeneration) exist as yet, but their severity often requires supportive medical intervention. Future Directions: These disorders provide unique insights into the role of selenoproteins in humans. The long-term consequences of reduced cellular antioxidant capacity remain unknown, and future surveillance of patients may reveal time-dependent phenotypes (e.g., neoplasia, aging) or consequences of deficiency of selenoproteins whose function remains to be elucidated. The role of antioxidant therapies requires evaluation. Antioxid. Redox Signal. 33, 481-497.

Keywords: SECISBP2; SEPSECS; TRU-TCA1-1; selenium; selenoprotein deficiency; thyroid hormone metabolism.

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Figures

FIG. 1.
FIG. 1.
Pathway of selenocysteine synthesis and its incorporation into selenoproteins. Sec is synthesized on its own tRNA (tRNA[Ser]Sec), which undergoes maturation through sequential modifications, with initial attachment of serine by SARS resulting in Ser-tRNA[Ser]Sec. Subsequent phosphorylation of this serine residue by PSTK generates O-Phosphoseryl-tRNA[Ser]Sec. Finally, SEPSECS catalyzes the acceptance of a selenophosphate, generated from selenide and ATP by SEPHS2, resulting in Sec-tRNA[Ser]Sec. An intermediate complex that includes Sec-tRNA[Ser]Sec, TRNAU1AP, and EEFSEC is subsequently formed. This complex is guided by an interaction with SECISBP2 to the SECIS-element of selenoprotein mRNA, ready for incorporation into the nascent polypeptide. Other factors (ribosomal protein L30, eukaryotic initiation factor eIF4a3, nucleolin, …) also have regulatory roles and influence the Sec insertion process. EEFSEC, Sec tRNA-specific eukaryotic elongation factor; mRNA, messenger RNA; PSTK, phosphoseryl-tRNA kinase; SARS, seryl-tRNA synthetase; Sec, selenocysteine; SECIS, SEleniumCysteine Insertion Sequence; SECISBP2, SECIS binding protein 2; SEPHS2, selenophosphate synthetase 2; SEPSECS, O-phosphoserine tRNA:Sec tRNA synthase; tRNA, transfer RNA; TRNAU1AP, tRNA selenocysteine 1 associated protein 1. Color images are available online.
FIG. 2.
FIG. 2.
Genomic organization of SECISBP2 and functional domains of SECISBP2 with the position of human mutations. (A) The organization of the SECISBP2 gene (top), with naturally occurring aminoterminal splice variants, each containing distal exons 8–17 shown next; the functional domains of SECISBP2 protein with the location of human mutations superimposed is shown (bottom). Arrowheads denote the location of ATG codons, which could function as alternative sites for the initiation of translation. Functional domains in SECISBP2 protein: N-terminal domain (1–399); minimal functional protein (shaded gray, 399–784); SID (399–517); minimal RBD (517–784); Lysine-rich domain involved in RNA specificity and ribosome binding (517–544); L7Ae homology module (620–745); NLS (380–390); redox-sensitive CRD (584–854); and two NES (NES1: 634–657; NES2: 756–770) (69). (B, C) Model of the L7ae RBD of SECISBP2. The position of wild-type residues (E679, C691) (B) and corresponding mutations (E679D, C691R) at these locations (C) is shown. The model was generated by using the phyre2 web portal, which predicts and analyzes protein structures based on homology/analogy to solved protein crystal structures (51). CRD, cysteine-rich domain; NES, nuclear export signals; NLS, nuclear localization signal; N-terminal, amino-terminal; phyre2, protein homology/analogy recognition engine 2; RBD, RNA-binding domain; SID, Sec incorporation domain. The figures were generated with MacPyMOL Molecular Graphics System, Schrödinger, LLC.
FIG. 3.
FIG. 3.
Genomic and structural organization of Sec-tRNA[Ser]Sec showing the position of human mutation. (A) The primary structure of human Sec-tRNA[Ser]Sec is shown in a cloverleaf model, with the location of C65G TRU-TCA1–1 mutation identified in the patient indicated (circled red). The acceptor stem constitutes paired 5′ and 3′ terminal bases, with the D arm, the anticodon arm, the variable arm, and the TψC arm depicted. Mammalian Sec-tRNA[Ser]Sec undergoes post-transcriptional modification at positions 34 (mcm5U or mcm5Um), 37 (i6A), 55 (ψ), and 58 (m1A). (B) Schematic of the TRU-TCA1-1 gene showing the coding region (black boxes) and regulatory elements (gray boxes) (43), with the location of C65G mutation identified in the patient. (C) The two Sec-tRNA[Ser]Sec isoforms, containing either mcm5U or mcm5Um modifications of the uracil at position 34 in the anticodon arm, differ from each other by a single methyl group on the 2′-O-ribosyl moiety. This reaction is catalyzed by an unknown methylase, and abundance of the mcm5Um isoform increases with selenium concentration (19). (D) Crystal structure showing catalytic and non-catalytic dimers of the SEPSECS tetramer bound to tRNA[Ser]Sec (71), with the position of the C65 nucleotide indicated. Other nucleotides in tRNA[Ser]Sec (cyan) and amino acids in SEPSECS (yellow) involved in RNA–protein interaction are also highlighted, as are the nucleotides (red) toward the position of Sec and the pyridoxal-5-phosphate substrate (green) within the catalytic domain. (E) A close-up of the structure around C65, showing H-bonds (dashed green lines) formed between C64 and the C64–C65 backbone with residues (E37 and K38) situated in helix 1 (H1) of the non-catalytic dimer of SEPSECS. mcm5U, 5-methoxycarbonyl-methyluridine; mcm5Um, 5-methoxycarbonylmethyl-2′-O-methyluridine. Color images are available online.
FIG. 4.
FIG. 4.
Genomic and structural organization of SEPSECS with the positions of the human mutations. (A) The organization of human SEPSECS gene (top) and schematic of SEPSECS protein (bottom) with the location of human mutations superimposed. Arrowheads denote the location of the ATG start codon. (B) Crystal structure showing a single catalytic–non-catalytic dimer from the complex bound to tRNA[Ser]Sec, with the position of all the human SEPSECS point mutations superimposed (71). Mutations associated with early onset (red) or late onset (yellow) disease and the pyridoxal-5-phosphate (cyan) substrate are highlighted. Color images are available online.
FIG. 5.
FIG. 5.
Detailed views comparing wild-type SEPSECS crystal structure and mutated amino acids modeled in the SEPSECS crystal structure that cause either early onset (red) or late onset (yellow) disease (71). Hydrogen bonds (dotted green lines), pyridoxal-5-phosphate substrate (cyan), tRNA (orange), and H2O (blue) are shown. The helices (H), beta-sheets (β), amino acids, and nucleotides involved in hydrogen bond networks or that are part of the active catalytic domain are labeled. Crystal structures for T325S and Y334C SEPSECS mutants are available and in the panels with these mutations an overlay of wild type (gray) and mutant (cyan) is shown (73). The effect of these mutations is described in detail in section SEPSECS in main text. The model was generated by using the phyre2 web portal, which predicts and analyzes protein structures based on homology/analogy recognition to solve protein crystal structures (51). The figures were generated with MacPyMOL Molecular Graphics System, Schrödinger, LLC. Color images are available online.
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