Nascent peptide assists the ribosome in recognizing chemically distinct small molecules

Area of Science:

• Molecular Biology
• Genetics
• Microbiology

Background:

• Gene expression regulation is vital for cell survival in changing environments.
• Macrolide antibiotics bind ribosomes, arresting translation at specific leader sequences (ermCL, ermBL) to induce antibiotic resistance genes (ermC, ermB).
• Erythromycin (ERY) arrests ermCL translation, while both ERY and telithromycin (TEL) stall ermBL translation, but the mechanism of molecular discrimination by the ribosome remains unclear.

Purpose of the Study:

• To investigate how ribosomes differentiate between chemically similar small molecules like macrolide antibiotics.
• To understand the role of nascent peptides in mediating ribosomal responses to antibiotic cues.
• To explore the potential for modulating gene activation pathways through alterations in protein sequences.

Main Methods:

• Investigated the effect of single amino acid substitutions in leader peptides on translation stalling.
• Analyzed the specificity of ribosomal response to different macrolide antibiotics (erythromycin and telithromycin).
• Assessed the impact of these changes on the induction of antibiotic resistance genes.

Main Results:

• Single amino acid changes in the leader peptide switched the specificity of macrolide recognition by the ribosome.
• These mutations altered gene activation in response to ERY alone, TEL alone, or both antibiotics.
• Specific mutations also prevented translation stalling altogether, demonstrating tunable ribosomal sensitivity.

Conclusions:

• The ribosome's response to chemical signals, such as macrolide antibiotics, can be modulated by subtle changes in the nascent peptide sequence.
• Nascent peptide sequences can be optimized to fine-tune translational sensitivity to environmental cues, impacting gene expression.
• This mechanism provides a basis for understanding how cells adapt antibiotic resistance and highlights the plasticity of translational regulation.