Programmed drug‐dependent ribosome stalling

Abstract

SummaryThe ribosome has the intrinsic capacity to monitor the sequence and structure of the nascent peptide. This fundamental property of the ribosome is often exploited in regulation of gene expression, in particular, for activation of expression of genes conferring resistance to ribosome-targeting antibiotics. Induction of expression of these genes is controlled by the programmed stalling of the ribosome at a regulatory open reading frame located upstream of the resistance cistron. Formation of the stalled translation complex depends on the presence of an antibiotic in the ribosome exit tunnel and the sequence of the nascent peptide. In this review, we summarize our current understanding of the molecular mechanisms of drug-and nascent peptide-dependent ribosome stalling.

The general mode of translation inhibition by macrolide antibiotics

“…3C) (14). The proline-containing sequences, corresponding to the ERY motif XP, are found at the sites of stalling in erm leader peptides of the "RP" class (27). Therefore, it appears that regulatory ORFs of many macrolide resistance genes have evolved by incorporating the most efficient ribosome stalling motifs allowing for robust induction of resistance when cells are exposed to macrolides.…”

“…For example, the RLR sequence, which is among the top stalling motifs for the TEL-or ERY-bound ribosome (Fig. 3 B and C), is the site of translation arrest at ermDL and several other regulatory ORFs controlling macrolide resistance genes (15,27). Translation of another leader ORF, ermBL, is halted when the ribosome reaches the VDK sequence, which matches one of the main ERY stalling motifs, XDK (Fig.…”

Recruitment of a species-specific translational arrest module to monitor different cellular processes

“…Such nascent chain-exit tunnel interactions serve as a widespread and critical mechanism of gene regulation (1)(2)(3)(4)(5)(6). In this mode of regulation, translation is accompanied by ongoing negotiation between the tunnel and the nascent polypeptide, which is in turn affected by either the nascent chain's engagement in protein localization or concentration of an antibiotic or a metabolic compound.…”

“…For instance, regulatory peptides encoded by leader regions of genes for resistance determinants against some antibiotics, such as erythromycin and chloramphenicol, undergo antibiotic-induced elongation arrest both in Gram-positive and Gram-negative bacteria (3,21,22). Clusters of positively charged amino acids can cause arrest in translation in eukaryotic ribosomes (23).…”

“…These studies revealed that the ribosome cannot necessarily complete translation of messages for any given amino acid sequences without any delay. Remarkably, programmed elongation arrest can serve as a novel mechanism of cellular regulation, for instance to monitor protein localization, metabolite concentration, and reception of an antibiotic (1)(2)(3)(4)(5)(6). Although regulatory nascent peptides having divergent stall-inducing amino acid sequences have been identified from different living organisms, their species-specificity and exchangeability among different systems have not been explored.…”