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Molecular mechanism of drug and nascent peptide-dependent ribosome stalling

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Title: Molecular mechanism of drug and nascent peptide-dependent ribosome stalling
Author(s): Ramu, Haripriya
Advisor(s): Mankin, Alexander
Contributor(s): Federle, Michael; Liebman, Susan; Freitag, Nancy; Lavie, Arnon
Department / Program: Medicinal Chemistry and Pharmacognosy
Graduate Major: Pharmacognosy
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): Translation attenuation Ribosome stalling Nascent peptide Macrolides
Abstract: The ability to monitor the nascent peptide structure and respond functionally to specific nascent peptide sequences is a fundamental property of the ribosome. An extreme manifestation of such a response is nascent peptide-dependent ribosome stalling, involved in the regulation of gene expression. Examples of bacterial genes regulated by programmed ribosome stalling include secA, tna and ermC. These genes contain an upstream regulatory ORF during the translation of which, ribosome stalling occurs, resulting in upregulation of the downstream gene. For ribosome stalling, the sequence of the nascent peptide encoded by the upstream ORF is critical. In case of ermC, ribosome stalling is also dependent on the presence of a specific antibiotic. The molecular mechanisms of programmed translation arrest are unclear. By using bioinformatics, we carried out a systematic analysis of the upstream regions of inducible macrolide resistance genes and identified various putative regulatory ORFs. The sequences of the peptides encoded in these ORFs were found to contain common sequence motifs, based on which we classified the leader peptides into different groups. Analysis of representative ORFs from each group revealed that programmed ribosome stalling occurs during translation. Investigation of the role of the antibiotic in ribosome stalling revealed that different peptides can cooperate with different antibiotics in order to cause translation arrest. By detailed analysis of ribosome stalling at the regulatory cistron of the ermA resistance gene, we uncovered a carefully orchestrated cooperation between the ribosomal exit tunnel and the A-site of the peptidyltransferase center in halting translation. The presence of an inducing antibiotic and a specific nascent peptide in the exit tunnel abrogate the ability of the peptidyltransferase center to catalyze peptide bond formation with a subset of amino acids. The extent of the conferred A-site selectivity is modulated by the C-terminal segment of the nascent peptide, where the third-from-last residue plays a critical role.
Issue Date: 2012-12-07
Genre: thesis
Rights Information: Copyright 2011 Haripriya Ramu
Date Available in INDIGO: 2012-12-07
Date Deposited: 2011-08

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