Structure of the mammalian ribosome as it decodes the selenocysteine UGA codon

  • Science. 2022 Jun 17;376(6599):1338-1343. doi: 10.1126/science.abg3875.
Tarek Hilal  1 ,  Benjamin Y Killam  2 ,  Milica Grozdanović  2 ,  Malgorzata Dobosz-Bartoszek  2 ,  Justus Loerke  1 ,  Jörg Bürger  1  3 ,  Thorsten Mielke  3 ,  Paul R Copeland  4 ,  Miljan Simonović  2 ,  Christian M T Spahn  1
Affiliations
  • 1. Institut für Medizinische Physik und Biophysik, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • 2. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 3. Max-Planck Institut für Molekulare Genetik, 14195 Berlin, Germany.
  • 4. Department of Biochemistry and Molecular Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
PMID: 35709277 DOI: 10.1126/science.abg3875
Abstract

The elongation of eukaryotic selenoproteins relies on a poorly understood process of interpreting in-frame UGA stop codons as selenocysteine (Sec). We used cryo-electron microscopy to visualize Sec UGA recoding in mammals. A complex between the noncoding Sec-insertion sequence (SECIS), SECIS-binding protein 2 (SBP2), and 40S ribosomal subunit enables Sec-specific elongation factor eEFSec to deliver Sec. eEFSec and SBP2 do not interact directly but rather deploy their carboxyl-terminal domains to engage with the opposite ends of the SECIS. By using its Lys-rich and carboxyl-terminal segments, the ribosomal protein eS31 simultaneously interacts with Sec-specific transfer RNA (tRNASec) and SBP2, which further stabilizes the assembly. eEFSec is indiscriminate toward l-serine and facilitates its misincorporation at Sec UGA codons. Our results support a fundamentally distinct mechanism of Sec UGA recoding in eukaryotes from that in bacteria.