The „selenosome“: choreography of reprogramming

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Cryo-electron microscopy makes cellular structures visible

Struktur des „Selenosoms“ © Charité | C. M. T. Spahn (
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Berlin, 27.06.2022

A team led by researchers at the Charité – Universitätsmedizin Berlin has succeeded in elucidating a fundamental process in molecular biology: the incorporation of the so-called 21st amino acid selenocysteine into so-called selenoproteins. These special protein constructs are vital for mammals, humans, but also some microorganisms. How they are formed and assembled in the body was unknown until now. In the scientific journal Science*, the authors describe for the first time in detail how a special binding pocket in interaction with various other factors makes this process possible.

Selenoproteins are an unusual group of proteins that have not been known for very long. It is assumed that there are up to 50 of these proteins, only some of which have been researched so far. They all have a complex structure and contain at least part of the eponymous amino acid selenocysteine (Sec) in their centre. Selenoproteins take on important protective and defensive functions in the cell and in the human body. Above all, they function as so-called oxidoreductases, i.e. mediators of central chemical reactions, and as thyroid hormones. It is also suspected that selenoproteins contribute to protection against tumours because they carry the element selenium and can quickly counteract oxidative stress.

But how do these special proteins come about? How does the molecular choreography work in the incorporation of selenocysteine during the assembly of the proteins, the protein biosynthesis? And what exactly is the structure of the „selenosome“, the complex that forms to produce selenoproteins? The team led by Prof. Dr. Christian Spahn, Director of the Institute of Medical Physics and Biophysics, and Dr. Tarek Hilal, Institute of Chemistry and Biochemistry at Freie Universität Berlin, together with partners at the Max Planck Institute for Molecular Genetics, the University of Illinois, Chicago, and Rutgers-Robert Wood Johnson Medical School, New Jersey, were able to use high-resolution, three-dimensional cryo-electron microscopy to understand this fundamental molecular biological process structurally and mechanistically.

Ribosomes, the protein factories of the cell, normally produce proteins strictly according to the blueprints provided by messenger RNAs (mRNAs). The universal genetic code uses specific sequences, each consisting of three varying bases, the mRNA triplet codons, to define which amino acid is incorporated at which position in a protein. Selenoproteins, however, have a special structure, so that the 20 standard amino acids are not sufficient for them. They contain the so-called 21st amino acid, selenocysteine (Sec), at certain positions.

Since there is no separate codon, i.e. no encoding base sequence, for the insertion of selenocysteine, a fundamental peculiarity arises during the construction of selenoproteins in the ribosomal complex. Through a separate signal sequence in the mRNA, the so-called SECIS element (SElenoCysteine insertion sequence), the ribosome is reprogrammed and the genetic information is virtually overwritten. A codon that normally programs a chain termination and thus the completion of the protein (UGA stop codon) becomes a new codon at the desired positions, namely the codon for the incorporation of selenocysteine. This recoding process requires, in addition to the SECIS element, a special transfer RNA loaded with selenocysteine (tRNASec) and additional, specialised translation factors. „Although the players involved have been known for several years, it has remained a mystery until now exactly how they function and how they interact,“ says Prof. Spahn. „In particular, how in detail the SECIS element works was mysterious, because it is not located in the immediate vicinity of the reprogrammed UGA stop codon in the linear sequence of the mRNA, but at the end, many hundreds of nucleotide building blocks away.“

To elucidate the molecular mechanism, the research team mimicked the ribosomal complex that forms to recode the UGA stop codon, the „selenosome“, in the lab. The high-resolution imaging technique of cryo-electron microscopy enables three-dimensional imaging of the tiny construct and thus structural studies. „Based on the imaged structures, we were able to elucidate how the factors involved interact with the ribosome and how exactly they interact to reprogramme the ribosome,“ explains Prof. Spahn. „In particular, we were able to show that the mRNA forms a large loop so that the UGA stop codon and the SECIS element are simultaneously bound to the ribosome. The SECIS element is thereby anchored to the ribosome in a previously unknown binding pocket and can then, in the ribosome-bound state, promote selenocysteine incorporation supported by translational factors.“ This structure and the functioning of the „selenosome“ surprised the research team and could not have been predicted. This is because the process in mammals and humans is significantly different from the incorporation of selenocysteine in bacteria, which was already known before. The complex now described exemplifies how signalling structures at the back end of an mRNA, i.e. outside the coding region, can interact with the ribosome to regulate it.

The researchers were thus able to elucidate the first step in the incorporation of selenocysteine. The subsequent steps are still unclear and will be structurally investigated in further work. Studies like this help to better understand the function and significance of the vital trace element selenium in normal physiology and in the development of diseases like diabetes or cancer. The work was made possible by the German Research Foundation (SFB740 and FOR1805) and grants from the German Research Foundation and the State of Berlin for large-scale equipment, in accordance with Article 91b of the German Constitution (GG).

*Hilal T et al. Structure of the mammalian ribosome as it decodes the selenocysteine UGA codon. Science 2022 Jun 17. doi: 10.1126/science.abg3875

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Originalpublikation
Institut für Medizinische Physik und Biophysik
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