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Scientists visualise crucial step in protein production in bacteria
24-01-2025
Researchers have visualized for the first time how mRNA is delivered to the ribosome to begin production of proteins. They solved 9 of the structures using the ESRF’s cryo-EM. The results are published in Science.
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Our DNA holds the instructions for making proteins, which are essential for the body to function. To use these instructions, a molecular machine called RNA polymerase (RNAP) copies the relevant section of DNA into a short-lived copy called messenger RNA (mRNA). This mRNA carries the instructions to another molecular machine, the ribosome. In bacteria, these two steps happen at the same time, allowing RNAP and the ribosome to cooperate and regulate each other.
A team led by Albert Weixlbaumer at the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) in Strasbourg, France, wanted to know how bacterial ribosomes are recruited to mRNAs, while they are still transcribed by RNAP. Using cryo-electron microscopy (cryo-EM), they studied complexes where an mRNA emerging from RNA polymerase (RNAP) was bound to the ribosome's small subunit.
The team used cryo-EM at the ESRF and at IGBMC to visualize the ribosome-mRNA assemblies at molecular resolution. This enabled them to observe the process in great detail. The cryo-EM experiments at the ESRF provided the structure of 9 of the complexes studied. “Access to high-end cryo-EM instruments is absolutely essential and represents the culmination of our work. It is a real pleasure to work with the scientists at the ESRF, we always feel they are very dedicated to the projects they support and the data quality and amount of date we obtain could not be better”, explains Albert Weixlbaumer, leader of the team and researcher at the IGBMC.
Complementary single-molecule fluorescence co-localization experiments carried out in the lab of Nils Walter (University of Michigan, USA) and in vivo crosslinking followed by mass spectrometry carried out in the lab of Juri Rappsilber (Technical University Berlin, Germany) suggest RNAP and the ribosome cooperate to facilitate recruitment of the small ribosomal subunit to the mRNA.
Intricate machines
“Our research reveals how these molecules work like intricate machines. I am always amazed that it is possible to reconstitute such an intricate and biologically fundamental process in a tube in the laboratory,” says Michael Webster, now a group leader at the John Innes Centre in the UK and one of the lead authors of the study which was published in Science.
“It is particularly exciting to have the opportunity to use powerful imaging techniques to answer questions that researchers have been interested in for a long time,” he adds.
The coupling of transcription and translation is conserved across many bacteria and causes new functions to emerge. The findings present opportunities for the research community to study how bacteria establish coupling in the first place and may provide new avenues to target bacterial gene expression by antibiotics.
The next steps will be to study how RNAP and the ribosome are able to regulate each other’s activities. For example, RNAP frequently pauses transcription and this is an important regulatory mechanism in gene expression. The team will aim to find out how the two machineries deal with these situations.
Reference:
Webster, M. W., et al. (2024). Molecular basis of mRNA delivery to the bacterial ribosome. Science. doi.org/10.1126/science.ado8476.
Text by Montserrat Capellas Espuny
Top image: This image highlights two alternative pathways for ribosome recruitment to an mRNA that is still being synthesized by RNA polymerase. RNA polymerase (left, red) can directly deliver the mRNA to the entry channel of the small ribosomal subunit (left, yellow). Alternatively, and likely dominant in vivo, RNA polymerase (green) can interact with ribosomal protein bS1 (right, cyan). bS1 binds and guides the mRNA (right, white and glowing) from RNA polymerase into the ribosome (right, yellow).