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Final Report Summary - TRANSARREST (Translational Regulation of Gene Expression by the Nascent Polypeptide Chain)

Ribosomes are large molecular factories that translate genetic information into the wide array of proteins needed for life. During translation, nascent proteins cross a large cavity within the ribosome, known as the exit tunnel, prior to being released into the cell. In some cases, nascent proteins known as arrest peptides cause ribosomes to stall by making stable contacts with the exit tunnel, which in turn impacts how other genes are regulated. What’s more, arrest peptides often require the help of a small molecule, a property that certain bacteria have exploited to become resistant to antibiotics (1). The goal of this CIG was to gain insights into the molecular mechanisms and functional diversity of arrest peptides.

First, we sought to understand how arrest peptides block translation by obtaining the three-dimensional structure of a bacterial ribosome stalled during the translation of a short arrest peptide in the presence of erythromycin, a member of the macrolide family of antibiotics. To do so, we used cryo-electron microscopy, a technique that has revolutionized our ability to capture the molecular details of biological processes in recent years. This, in turn, allowed us to establish the mechanism by which macrolide antibiotics block the translation of certain proteins in bacteria (2). In parallel, we showed how antimicrobial peptides produced by the innate immune response block translation by binding to the exit tunnel of the bacterial ribosome (3, 4). Ultimately, these data could help design new antimicrobials to counter multidrug-resistant bacteria.

Second, we set to systematically assess the functional diversity of arrest peptides. Doing so required us to develop a new tool, which we call inverse toeprinting. In a nutshell, this method allows us to monitor the ribosome stalling potential of >1011 peptides, making it possible to identify novel arrest peptides or characterize existing ones (5). We used inverse toeprinting to analyze the stalling landscape of free and antibiotic-bound bacterial ribosomes. In time, we will use inverse toeprinting to decipher the rules underlying peptide-mediated ribosome stalling and to systematically assess the natural occurrence of arrest peptides.

Finally, this CIG helped me establish my group at IECB (Inserm U1212) in France. The support provided was key to obtaining the preliminary data needed to secure other sources of funding, including a grant from the ANR (2014), an installation grant from IdEx-Bordeaux (2014) and an ERC Consolidator grant (2017). During this CIG, I secured a tenured Inserm position, expanded the size of my group, developed a European network of collaborators and attended a number of meetings in my field. The increased national and international visibility resulting from our research activities also contributed to my being selected as an EMBO Young Investigator and to being awarded the Coups d’Elan Prize for French Research from the Bettencourt-Schueller Foundation.

(1) Seip & Innis (2016) J Mol Biol 428, 2217
(2) Seefeldt et al., manuscript in preparation
(3) Seefeldt et al. (2015) Nat Struct Mol Biol 22, 470
(4) Seefeldt et al. (2016) Nucleic Acids Res 44, 2429
(5) Seip et al. (2018) bioRχiv, doi:

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