Post-Transcriptional Control of Selenoprotein Biosynthesis

Abstract

Selenoproteins are defined as proteins containing the 21st proteinogenic amino acid, selenocysteine (Sec). Sec is encoded by UGA (STOP) codons which are re-coded to Sec by the presence of a selenocysteine insertion sequence (SECIS) element in the 3'-untranslated region of selenoprotein mRNAs. The SECIS element is bound by several proteins, including SECIS-binding protein 2 (SBP2). Translation of selenoproteins critically depends on the integrity of the SECIS element - SBP2 interaction. Mutations in a SECIS element can abrogate expression of the respective selenoprotein. Mutations in SBP2 impinge on biosynthesis of a subset of selenoproteins and lead to a syndrome including hormonal, neurological, immunological symptoms as well as myopathy. Several other RNA-binding proteins are involved in selenoprotein translation and mediate the hierarchical response of selenoproteins to selenium deficiency. Global inhibition of selenoprotein translation is lethal in the mouse and hypomorphic mutations in selenocysteine synthase in humans leads to Progressive Cerebello Cerebral Atrophy, a neurodevelopmental and neurodegenerative disease in pediatric patients.

Selenium and selenocysteine: roles in cancer, health, and development

“…In bacteria, SECIS elements are more simplified and occur within the coding regions immediately downstream of the UGA codon. They serve as the attachment site for the specific elongation factor, SelB, which is brought to the ribosome in a complex with Sec-tRNA [Ser]Sec [45]. The insertion of Sec in archaea and eukaryotes is more complex and involves additional factors.…”

“…The insertion of Sec in archaea and eukaryotes is more complex and involves additional factors. The specific elongation factor, EFsec, forms a complex with Sec-tRNA [Ser]Sec (EFsec-Sec-tRNA [Ser]Sec ) that binds to the SECIS binding protein 2 (SBP2)-SECIS complex and the ribosome [45]. In addition, there are at least three other factors, ribosomal protein L30 [46], nucleolin [47] and eukaryotic initiation factor (eIF4a3) [48], that have roles in Sec insertion into protein.…”

Secisbp2 Is Essential for Embryonic Development and Enhances Selenoprotein Expression

“…These include L30 (Rpl30), which is a component of the UGA recoding machinery (14), YB1 (48), NSEP1 (47), eIF4a3 (9), and nucleolin (33,56), which play roles in regulating UGA recoding. In addition, Secisbp2L binds to SECIS elements, but does not support Sec incorporation (19) [reviewed in Seeher et al (44)]. …”

Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice

“…The SECIS forms a kink-turn structure, which is bound by SECIS-binding protein 2 (Secisbp2). Secisbp2 enhances selenoprotein expression and stabilizes selenoprotein mRNAs [2]. Sec is synthesized attached to its tRNA [Ser]Sec , which is initially charged with serine, phosphorylated to pSer-tRNA [Ser]Sec , and finally converted to Sec-tRNA [Ser]Sec by selenocysteine synthase (SepSecS) [3, 4].…”