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The secret of the end of translation: What is the magical role of the release factor?
In genetic biology, release factors play a crucial role, especially in the final stages of protein synthesis. These specialized proteins recognize stop codons in messenger RNA (mRNA), thereby facilitating the termination of translation. Understanding this process not only reveals the mysteries of the inner workings of cells, but also opens a new window for scientists to study more complex life phenomena.
“The presence of release factors allows newly synthesized polypeptides to be released from the ribosomes smoothly, otherwise they will not be able to complete the production.”
During the translation of mRNA, most codons are recognized by "charging" tRNA molecules called aminoacyl-tRNAs. According to the standard genetic code, there are three stop codons in mRNA: UAG ("amber"), UAA ("yellow"), and UGA ("protein" or "ambient"). Although these stop codons look like normal codons, they are not translated by tRNA. In 1967, scientist Mario Capecchi first proposed that the so-called release factor was not tRNA, but a protein.
Release factors are divided into two major categories. The first class of release factors recognizes the stop codon by binding at the A site of the ribosome, mimicking the binding of tRNA, and disassembles the ribosome when the polypeptide is released. The second type of release factor is GTPase, which is responsible for enhancing the activity of the first type of release factor and helping it dissociate from the ribosome. Bacterial released factors include RF1, RF2 and RF3. In eukaryotes and archaea, the names of these release factors were changed to "eRF", which means "eukaryotic release factor".
"The evolution of release factors shows separate developments between bacterial and archaeal-eukaryotic release factors, reflecting the diversity of life evolution."
In terms of structure and function, scientists have solved the crystal structures of 70S ribosomes and three release factors of various bacteria, showing the details of RF1 and RF2 in stop codon recognition. In addition, the cold EM structures of the eukaryotic 80S ribosome when bound to eRF1 and eRF3 also provided further insights. These structures help us understand that even small changes in the termination process can affect the entire translation machinery.
For bacterial release factors, they are mainly composed of four domains. Each domain has its own specific catalytic properties and functions. In particular, the "tripeptide anti-codon" structure in the second domain is crucial for the recognition of the stop codon. Only one residue in this conformation participates in this process through hydrogen bonding, whereas the GGQ motif in domain III is essential for peptidyl-tRNA hydrolase (PTH) activity.
In a similar structure in eukaryotes, eRF1 is divided into four domains. The N-terminal domain is mainly responsible for the recognition of the stop codon, while the M domain and C domain function in the process of polypeptide release. The coordinated action of release factors is essential for the integrity of RNA synthesis. In this system, when eRF3 hydrolyzes GTP, a change in positioning allows GGQ to enter the peptide transfer center (PTC) to promote hydrolysis.
"Through the action of release factors, the ribosome can not only effectively release the synthesized protein, but also prepare to participate in the subsequent translation process again."
Advances in technology have enabled us to glimpse these complex biological processes and gain a deeper understanding of them. Moreover, research on release factors not only has a profound impact on the field of molecular biology, but may also bring new possibilities for application in the medical field, especially in the development of new therapies and drugs.
How can further research on release factors help us unlock more doors to the mysteries of life?
