The essential balance of redox reactions, protein synthesis and folding, protection of cell membranes, and integrity of genomic DNA depends on a handful of proteins called selenoproteins that include the trace element selenium in the form of the amino acid selenocysteine.

Usually, ribosomes halt on mRNA strands when they encounter a UGA codon. But for some mRNAs in all forms of life, the genetic code is recoded to incorporate selenocysteine instead. This process essential to life, that interprets in-frame UGA stop codons as selenocysteine is poorly understood.

Paul Copeland, PhD, a professor in the Department of Biochemistry and Molecular Biology at Rutgers Robert Wood Johnson Medical School, is an author of the study.

An international team including scientists from the Institute for Medical Physics and Biophysics, and the Max Planck Institute for Molecular Genetics in Berlin, the University of Illinois in Chicago and Rutgers University in Piscataway, have used cryo-electron microscopy to visualize the recoding of selenocysteine-UGA in mammals for the first time, and determine that the mechanism is fundamentally different in eukaryotes and bacteria.

Their findings were published last week in and article in the journal Science Structure of the mammalian ribosome as it decodes the selenocysteine UGA codon.” The authors claim understanding the mechanisms involved in the inclusion of selenocysteine-UGA is critical for the development of new medical therapies. Diseases, including cancer, heart disease, Alzheimer’s, male infertility and diabetes are linked to selenoproteins.

“This work revealed structures that had never before been seen, some of which are unique in all of biology,” said Paul Copeland, a professor in the Department of Biochemistry and Molecular Biology at Rutgers Robert Wood Johnson Medical School, who is an author of the study.

Using specialized cryo-electron microscopy, stop-motion animation, and computational tools, the team discerned how the translational machinery works to dictate the function of the ribosome in incorporating selenocysteine.

“This amino acid gets attached to a unique RNA molecule that has to be carried to the ribosome via a unique protein factor,” said Copeland, whose lab has spent the past two decades unraveling the selenocysteine incorporation process. “And all of this evolved in humans specifically to allow selenium to be incorporated into this handful of proteins.”

The authors demonstrate that during the process of selenocysteine incorporation, an RNA-protein complex forms between the noncoding selenocysteine-insertion sequence (SECIS) in the selenoprotein mRNA, SECIS-binding protein 2 (SBP2), and 40S ribosomal subunit, which enables the selenocysteine-specific translation elongation factor, eEFSec, to deliver the unique amino acid. The researchers show that the translation elongation factor and SBP2 do not physically interact but use these carboxyl tails to engage opposite ends of the noncoding selenocysteine-insertion sequence. At the same time, the ribosomal protein eS31 binds selenocysteine-specific transfer RNA (tRNASec) and SBP2, which increases the stability of the complex.

The authors also show that the elongation factor for selenocysteine eEFSec, can also engage another amino acid, L-serine, which can mis-incorporate serine at selenocysteine-UGA codons.

Copeland hopes to one day be able to specifically regulate the expression of selenoproteins in vivo. To achieve this, his team continues to probe into the factors that contribute to selenocysteine incorporation in the zebrafish model.

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