Cracking the final code: eRF1’s mission in stop codon recognition

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During the process of translation, different codons in our mRNA are recognised by specific tRNA molecules to synthesise the proteins in our body. However, what happens when a STOP codon is encountered? Despite not having a tRNA match, there is always a perfect soulmate that recognises you for who you are! In 2000 Song and colleagues used a technique called crystallography to help us understand how this process works. They focused on two proteins that are essential for translation termination in eukaryotes: eRF1 and eRF3. These are called release factors, because they help the ribosome release the protein chain.
Song and his team found out that eRF1 has three domains, or parts, that have different roles. The first domain, called N, has a groove with a special sequence of amino acids called NIKS. This is where eRF1 recognises the stop codons, which are the signals for the ribosome to stop. The second domain, called M, has another special sequence called GGQ, which sticks out from the rest of the molecule. This is where eRF1 breaks the bond between the last tRNA and the protein chain, freeing the protein. The third domain, called C, is where eRF1 interacts with eRF3, which is a helper protein that helps eRF1 bind to the ribosome and change its shape. By changing them and seeing what happens, Song and his team showed that these domains and sequences are very important for termination of translation. They also compared eRF1 to tRNA, and found that they are similar in structure and function, except that tRNA adds amino acids to the protein chain, while eRF1 releases it. This is an amazing example of molecular mimicry, where one molecule copies another to do a specific job.
By showing the structure and mechanism of eRF1 and eRF3, Song and his team made a huge contribution to our knowledge of the termination of translation, which is essential for all living cells. But why is this so important? Because understanding release factors could help us treat many diseases caused by mutations that create premature stop codons. There are drugs that can make translation continue past these stop codons, by interfering with the release factor complex. These drugs make the ribosome accept a wrong tRNA instead of stopping. This is a new field of research that could offer new hope for people with genetic diseases.
Creator: Eunji (Ellen) Im
References:
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Mutations in the highly conserved GGQ motif of class 1 polypeptide release factors abolish ability of human eRF1 to trigger peptidyl-tRNA hydrolysis. Frolova LY, Tsivkovskii RY, Sivolobova GF, Oparina NY, Serpinsky OI, Blinov VM, Tatkov SI, Kisselev LL. RNA. 1999 Aug;5(8):1014-20. doi: 10.1017/s135583829999043x.
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Ataluren binds to multiple protein synthesis apparatus sites and competitively inhibits release factor-dependent termination. Huang S, Bhattacharya A, Ghelfi MD, Li H, Fritsch C, Chenoweth DM, Goldman YE, Cooperman BS. Nat Commun. 2022 May 6;13(1):2413. doi: 10.1038/s41467-022-30080-6.
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