Anti-peptidyl transferase leader peptides of attenuation-regulated chloramphenicol-resistance genes.

Gu, Zhiping; Harrod, Robert; Rogers, Elizabeth; Lovett, Paul S.

doi:10.1073/pnas.91.12.5612

Cited by 56 publications

(70 citation statements)

References 32 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Chiba

Kanamori

Ueda

et al. 2011

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

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Nascent chain-mediated translation arrest serves as a mechanism of gene regulation. A class of regulatory nascent polypeptides undergoes elongation arrest in manners controlled by the dynamic behavior of the growing chain; Escherichia coli SecM monitors the Sec protein export pathway and Bacillus subtilis MifM monitors the YidC membrane protein integration/folding pathway. We show that MifM and SecM interact with the ribosome in a speciesspecific manner to stall only the ribosome from the homologous species. Despite this specificity, MifM is not exclusively designed to monitor membrane protein integration because it can be converted into a secretion monitor by replacing the N-terminal transmembrane sequence with a secretion signal sequence. These results show that a regulatory nascent chain is composed of two modular elements, one devoted to elongation arrest and another devoted to subcellular targeting, and they imply that physical pulling force generated by the latter triggers release of the arrest executed by the former. The combinatorial nature may assure common occurrence of nascent chain-mediated regulation.stalling sequence | SpoIIIJ | SecA | exit tunnel

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Section: Discussionmentioning

confidence: 99%

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

Chiba

Kanamori

Ueda

et al. 2011

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

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“…Members of both classes of peptides may function similarly on the basis of their common footprints on 23S rRNA and the sensitivity of the inhibitory activity to competition by erythromycin (10). The mechanism of peptide inhibition of PT is probably not identical to that of chloramphenicol since the activities of chloramphenicol and the peptides are additive (10).The anti-PT activity of the leader peptides is thought to play a critical role in the translation attenuation regulation of cat (1,8,11,13,17,26) and cmlA (6,33) by selecting the site of ribosome stalling (10,12). Thus, the in vivo synthesis of the inhibitor peptides coincides with the translation by a ribosome to the leader site at which ribosome stalling will activate downstream gene expression (1, 10).…”

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confidence: 99%

“…We have recently demonstrated that PT is also inhibited by the short peptides that are encoded by the leaders of attenuation regulated. chloramphenicol resistance genes (10,12). The peptide inhibitors fall into two classes according to their sizes and specific inhibition.…”

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confidence: 99%

“…The peptide inhibitors fall into two classes according to their sizes and specific inhibition. The leaders for inducible cat genes specify one class of PT-inhibitor peptides; the first five codons of the leaders encode 5-mer peptides that exhibit about 1/10 of the specific inhibition of chloramphenicol (10,12). The second class of inhibitor peptide consists of only one member, the eight-residue peptide that is encoded by the first eight codons of the cmlA leader (12).…”

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Properties of a pentapeptide inhibitor of peptidyltransferase that is essential for cat gene regulation by translation attenuation

Harrod

Rogers

et al. 1994

J Bacteriol

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Inducible chloramphenicol resistance genes cat and c*ml are regulated by translation attenuation. For both genes, the leader codons that must be translated to deliver a ribosome to the induction site specify a peptide that inhibits peptidyltransferase in vitro. The antipeptidyltransferase activity of the peptides is thought to select the site of ribosome stalling that is essential for Induction. Using variations of the cat-86 leader-encoded 5-mer peptide MVKTD, we demonstrate a correlation between the in vitro antipeptidyltransferase activity and the ability of the same peptide to support induction by chloramphenicol in vivo. MVKTD Peptide bond formation during translation is catalyzed by the ribosome-associated activity peptidyltransferase (PT) (21). PT is the target for several antibiotics including chloramphenicol and anisomycin (20). We have recently demonstrated that PT is also inhibited by the short peptides that are encoded by the leaders of attenuation regulated. chloramphenicol resistance genes (10, 12). The peptide inhibitors fall into two classes according to their sizes and specific inhibition. The leaders for inducible cat genes specify one class of PT-inhibitor peptides; the first five codons of the leaders encode 5-mer peptides that exhibit about 1/10 of the specific inhibition of chloramphenicol (10,12). The second class of inhibitor peptide consists of only one member, the eight-residue peptide that is encoded by the first eight codons of the cmlA leader (12). The cmlA 8-mer peptide is about one-half as inhibitory as chloramphenicol on SOS ribosomal subunits ofBacillus subtilis and is about fivefoldmore inhibitory than the cat leader peptides. Members of both classes of peptides may function similarly on the basis of their common footprints on 23S rRNA and the sensitivity of the inhibitory activity to competition by erythromycin (10). The mechanism of peptide inhibition of PT is probably not identical to that of chloramphenicol since the activities of chloramphenicol and the peptides are additive (10).The anti-PT activity of the leader peptides is thought to play a critical role in the translation attenuation regulation of cat (1,8,11,13,17,26) and cmlA (6,33) by selecting the site of ribosome stalling (10,12). Thus, the in vivo synthesis of the inhibitor peptides coincides with the translation by a ribosome to the leader site at which ribosome stalling will activate downstream gene expression (1, 10). Moreover, a missense mutation in the cat leader that prevents induction by chloram-* Corresponding author. Phone: (410) 455-2249. Fax: (410) 455-3875. phenicol causes an amino acid replacement in the 5-mer peptide that eliminates its anti-PT activity (12).In the present study we demonstrate that the in vitro inhibitory activity of a leader peptide correlates with the in vivo activity of the peptide in gene regulation. Examination of the peptide sensitivity of PT from several sources suggests that the target is a sequence or structure which is conserved in prokaryotic and eukaryotic ribosom...

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“…Studies in both eukaryotes and prokaryotes have demonstrated that uORF peptides can cause ribosomal stalling by various mechanisms, including interference with the peptidyl transferase center activity (Gu et al 1994;Lovett and Rogers 1996), thereby inhibiting translation termination by preventing peptidyl-tRNA hydrolysis (Janzen et al 2002) or by causing arrest of elongating or terminating ribosomes in response to a cellular signal (Luo et al 1995;Wang and Sachs 1997;Hood et al 2009). It is also noteworthy that studies have implicated the role of highly basic peptides in impeding translation, possibly by causing conformational changes in rRNA (Lovett and Rogers 1996).…”

Section: Discussionmentioning

confidence: 99%

Expression of a novel mRNA transcript for human microsomal epoxide hydrolase (EPHX1) is regulated by short open reading frames within its 5′-untranslated region

Nguyen

Yang

Omiecinski

2013

RNA

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Microsomal epoxide hydrolase (mEH, EPHX1) is a critical xenobiotic-metabolizing enzyme, catalyzing both detoxification and bioactivation reactions that direct the disposition of chemical epoxides, including the carcinogenic metabolites of several polycyclic aromatic hydrocarbons. Recently, we discovered that a previously unrecognized and primate-specific EPHX1 transcript, termed E1-b, was actually the predominant driver of EPHX1 expression in all human tissues. In this study, we identify another human EPHX1 transcript, designated as E1-b ′ . Unusually, both the E1-b and E1-b ′ mRNA transcripts are generated from the use of a far upstream gene promoter, localized ∼18.5 kb 5′ -upstream of the EPHX1 protein-coding region. Although expressed at comparatively lower levels than E1-b, the novel E1-b ′ transcript is readily detected in all tissues examined, with highest levels maintained in human ovary. The E1-b ′ mRNA possesses unusual functional features in its 5 ′ -untranslated region, including a GC-rich leader sequence and two upstream AUGs that encode for short peptides of 26 and 17 amino acids in length, respectively. Results from in vitro transcription/translation assays and direct transfection in mammalian cells of either the E1-b ′ transcript or the encoded peptides demonstrated that the E1-b ′ upstream open reading frames (uORFs) are functional, with their presence markedly inhibiting the translation of EPHX1 protein, both in cis and in trans configurations. These unique uORF peptides exhibit no homology to any other known uORF sequences but likely function to mediate posttranscription regulation of EPHX1 and perhaps more broadly as translational regulators in human cells.

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Anti-peptidyl transferase leader peptides of attenuation-regulated chloramphenicol-resistance genes.

Abstract: The chloramphenicol (Cm)-inducible emL4 gene of Tn1696 specifies nonenzymatic resistance to Cm and is regulated by attenuation.

Cited by 56 publications

References 32 publications

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

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

Properties of a pentapeptide inhibitor of peptidyltransferase that is essential for cat gene regulation by translation attenuation

Expression of a novel mRNA transcript for human microsomal epoxide hydrolase (EPHX1) is regulated by short open reading frames within its 5′-untranslated region

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