Features of Ribosome-Peptidyl-tRNA Interactions Essential for Tryptophan Induction of tna Operon Expression

Cruz-Vera, Luis R.; Rajagopal, Soumitra; Squires, Catherine L.; Yanofsky, Charles

doi:10.1016/j.molcel.2005.06.013

Cited by 131 publications

(274 citation statements)

References 34 publications

Supporting

Mentioning

263

Contrasting

Order By: Relevance

“…Mutations of such 23S rRNA residues (A2062, A2503, U1782, C2610) dramatically reduce the efficiency of stalling with ErmAL1 or ErmCL (15,19). Strikingly, neither these mutations nor changes of residues involved in recognition of other stalling peptides (G2583, U2584, U2586, A2587, U2609) (20)(21)(22) significantly affected arrest with the MRL peptide (Fig. S4).…”

Section: Resultsmentioning

confidence: 96%

Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Sothiselvam

Liu

Han

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

122

View full text Add to dashboard Cite

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

show abstract

Section: Resultsmentioning

confidence: 96%

Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Sothiselvam

Liu

Han

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

122

View full text Add to dashboard Cite

show abstract

“…Enzymes responsible for individual modifications were described in the following references Status of the U2504 modification in the strains expressing 23S rRNA with the U955C and U2580C mutations. The strain SQ171 lacking chromosomal rrn alleles 20 was transformed with either pLK35 plasmid expressing wild type rRNA or plasmid pUCUC carrying rrnB operon with the mutations U955C and U2580C in 23S rRNA gene. After plasmid exchange and verification that the strain expresses exclusively mutant ribosome, the rluC::kan allele was transduced from the strain JW1072 from the Keio collection 15 .…”

Section: Antibiotic Resistance Could Drive Acquisition and Maintenancmentioning

confidence: 99%

An Indigenous Posttranscriptional Modification in the Ribosomal Peptidyl Transferase Center Confers Resistance to an Array of Protein Synthesis Inhibitors

Toh

Mankin

2008

Journal of Molecular Biology

View full text Add to dashboard Cite

A number of nucleotide residues in ribosomal RNA undergo specific posttranscriptional modification. The roles of most modifications are unclear, but their clustering in the functionallyimportant regions of rRNA suggest that they might either directly affect the activity or assembly of the ribosome or modulate its interactions with ligands. Of the 25 modified nucleotides in E. coli 23S rRNA, 14 are located in the peptidyl transferase center, the main antibiotic target in the large ribosomal subunit. Since nucleotide modifications have been closely associated with both antibiotic sensitivity and antibiotic resistance, the loss of some of these posttranscriptional modifications may affect the susceptibility of bacteria to antibiotics. We investigated the antibiotic sensitivity of E. coli cells in which the genes of eight rRNA modifying enzymes targeting the PTC were individually inactivated. The lack of pseudouridine at position 2504 of 23S rRNA was found to significantly increase the susceptibility of bacteria to peptidyl transferase inhibitors. Therefore, this indigenous posttranscriptional modification may have evolved as an intrinsic resistance mechanism protecting bacteria against natural antibiotics.Posttranscriptional modifications in rRNA are ubiquitous. However, the functional significance of most of them remains obscure. Acquisition and maintenance through the course of evolution of a number of genes dedicated to rRNA modification in spite of the associated energetic and metabolic cost argue that the modified nucleotides in rRNA render competitive benefits for the species. Clustering of the modified nucleotides in the functional centers of the ribosome hint that some of them may help to fine-tune ribosome functions. Indeed, inactivation of certain modification enzymes was shown to either decrease the efficiency of protein synthesis or negatively affect ribosome assembly 1 -5 . Yet, in most cases, the lack of individual posttranscriptional modifications only marginally affects cell growth 6; 7 .The ribosome is one of the evolutionarily-preferred antibiotic targets. A large variety of natural antibiotics of microbial origin bind to the ribosomes of sensitive organisms and inhibit protein synthesis thereby providing competitive advantage to the antibiotic producers. One of the common ways in which antibiotic producers avoid suicide is by expressing HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript specific methyltransferase enzymes which modify rRNA residues in the drug target site, and thus prevent antibiotic binding to the ribosome 8; 9 . Acquisition of such genes by pathogens is one of the major causes of clinical resistance to a number of antibacterial drugs. However, not only acquisition of new rRNA modifications, but the lack of natural modifications may affect susceptibility of cells to antibiotics. In a few well-documented cases, the lack of natural modifications was shown to render cells resistant to specific antibiotics 10 -12 .Most of the antibioti...

show abstract

“…Because the spacing between Trp12 and the active site is important, an involvement of the nascent peptide itself in the signaling process appears likely (Gong and Yanofsky 2002). On the ribosome, Lys90 of L22 and U2609 of 23S rRNA are essential (Cruz-Vera et al 2005). Lys90 may interact with Trp12, while U2609 is located more closely to the PT center (z15 Å ), and thus may be involved in communication rather than recognition (Cruz-Vera et al 2005).…”

Section: Modulation Of the Hydrolytic Activity Of The Pt Centermentioning

confidence: 99%

Modulating the activity of the peptidyl transferase center of the ribosome

Beringer¹

2008

RNA

View full text Add to dashboard Cite

The peptidyl transferase (PT) center of the ribosome catalyzes two nucleophilic reactions, peptide bond formation between aminoacylated tRNA substrates and, together with release factor, peptide release. Structure and function of the PT center are modulated by binding of aminoacyl-tRNA or release factor, thus providing the basis for the specificity of catalysis. Another way by which the function of the PT center is controlled is signaling from the peptide exit tunnel. The SecM nascent peptide induces ribosome stalling, presumably by inhibition of peptide bond formation. Similarly, the release factor-induced hydrolytic activity of the PT center can be suppressed by the TnaC nascent peptide contained in the exit tunnel. Thus, local and long-range conformational rearrangements can lead to changes in the reaction specificity and catalytic activity of the PT center.

show abstract

Features of Ribosome-Peptidyl-tRNA Interactions Essential for Tryptophan Induction of tna Operon Expression

Cited by 131 publications

References 34 publications

Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Macrolide antibiotics allosterically predispose the ribosome for translation arrest

An Indigenous Posttranscriptional Modification in the Ribosomal Peptidyl Transferase Center Confers Resistance to an Array of Protein Synthesis Inhibitors

Modulating the activity of the peptidyl transferase center of the ribosome

Contact Info

Product

Resources

About