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Recognizes Transfer-Messenger RNA with Specificity; a Functional Complex Prior to Entering the Ribosome? Reynald Gillet, Brice Felden

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Recognizes Transfer-Messenger RNA with Specificity; a Functional Complex Prior to Entering the Ribosome? Reynald Gillet, Brice Felden Transfer RNA(Ala) recognizes transfer-messenger RNA with specificity; a functional complex prior to entering the ribosome? Reynald Gillet, Brice Felden To cite this version: Reynald Gillet, Brice Felden. Transfer RNA(Ala) recognizes transfer-messenger RNA with specificity; a functional complex prior to entering the ribosome?. EMBO Journal, EMBO Press, 2001, 20 (11), pp.2966-76. 10.1093/emboj/20.11.2966. inserm-00718204 HAL Id: inserm-00718204 https://www.hal.inserm.fr/inserm-00718204 Submitted on 16 Jul 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The EMBO Journal Vol. 20 No. 11 pp. 2966±2976, 2001 Transfer RNAAla recognizes transfer-messenger RNA with speci®city; a functional complex prior to entering the ribosome? Reynald Gillet and Brice Felden1 involved in cellular adaptation to lactose availability (Abo et al., 2000). tmRNA function is also required for the Laboratoire de Biochimie Pharmaceutique, Faculte de Pharmacie, Universite de Rennes I, UPRES Jeune Equipe 2311, IFR 97, ef®cient growth of Bacillus subtilis under various stresses 2 avenue du Pr LeÂon Bernard, 35043 Rennes, France (Muto et al., 2000). Altogether, evidence suggests that tmRNA expression becomes crucial when bacteria have to 1Corresponding author e-mail: [email protected] adapt to environmental changes. tmRNA acts initially as tRNA, being aminoacylated at tmRNA (SsrA or 10Sa RNA) functions as both a its 3¢ end with alanine by alanyl-tRNA synthetase (Komine transfer RNA and a messenger RNA, rescues stalled et al., 1994; Ushida et al., 1994), to add alanine to the ribosomes and clears the cell of incomplete polypep- stalled polypeptide chain. Resumption of translation tides. We report that native Escherichia coli tmRNA ensues not on the mRNA upon which the ribosomes interacts speci®cally with native or synthetic E.coli were stalled, but at an internal position in tmRNA. tRNA alanine (tRNAAla) in vitro, alanine being the Termination soon occurs and permits ribosome recycling. ®rst codon of the tmRNA internal open reading The current model is that aminoacylated tmRNA is ®rst frame. Aminoacylatable RNA microhelices also bind recruited to the ribosomal A site. Subsequently, the tmRNA. Complex formation was monitored by gel nascent polypeptide chain is transferred to the tRNA retardation assays combined with structural probes. portion of aminoacylated tmRNA. The ribosome trans- Nucleotides from the acceptor stem of tRNAAla are locates and the incomplete mRNA is replaced with the essential for complex formation with tmRNA. tRNAAla open reading frame (ORF) of tmRNA possessing a isoacceptors recognize tmRNA with different af®ni- termination codon (for a review see Karzai et al., 2000). ties, with an important contribution from tRNAAla Thus, tmRNA has a dual function in bacteria. First, as a post-transcriptional modi®cations. The most abundant tRNA, thanks to a partial structural analogy with canonical tRNAAla isoacceptor in vivo binds tmRNA with the tRNAs, and then as an mRNA, with an internal coding highest af®nity. A complex between tRNAAla and sequence that begins, in the vast majority of known tmRNA might involve up to 140 tmRNA molecules tmRNA sequences, with an alanine (resume) codon. out of 500 present per E.coli cell. Our data suggest Primitive versions of the translation apparatus were that tmRNA interacts with the tRNA that decodes proposed to be made solely of RNAs (Noller et al., 1992; the resume codon prior to entering the ribosome. Piccirilli et al., 1992). To study how protein synthesis may Biological implications of promoting speci®c com- have looked some 3.8 billion years ago, before protein- plexes between tmRNA and aminoacylatable RNAs based life emerged, one might contemplate designing an are discussed, with emphasis on primitive versions of `all RNA' system that can form a peptide bond. Recent the translation apparatus. structural (Nissen et al., 2000) and functional (Muth et al., Keywords: evolution/protein synthesis/tRNAAla/tmRNA/ 2000) evidence suggests that the ribosome is a catalytic trans-translation RNA (ribozyme), and also that an aminoacyl-tRNA synthetase ribozyme can aminoacylate a tRNA (Lee et al., 2000). Also, iterative RNA selection previously identi®ed ribozymes that form amide bonds between RNA Introduction and an amino acid, or between two amino acids (Zhang In bacteria, transfer-messenger RNA (tmRNA), known and Cech, 1997). alternatively as SsrA RNA or 10Sa RNA, rescues stalled In today's cellular protein factory, the ribosome ribosomes and contributes to the degradation of incom- orchestrates the process of protein synthesis, bringing pletely synthesized peptides. As an ancillary role (Huang tRNAs and mRNAs into proximity (Figure 1A). There are et al., 2000), this RNA encodes a peptide tag that is intrinsic assets in selecting tmRNA as a model to form a incorporated at the end of the aberrant polypeptide and peptide bond without the help of ribosomal proteins targets it for proteolysis. This process, referred to as trans- (Figure 1B). First, tmRNA consists of a single poly- translation, is frequent when Escherichia coli cells grow, ribonucleotide chain that sustains two main functions in but is not essential. The gene encoding tmRNA is, protein synthesis: (i) the adapter between the genetically however, considered essential for Mycoplasma genitalium encoded message and the newly synthesized polypeptide and Mycoplasma pneumoniae (Hutchison et al., 1999), and (tRNA function), and (ii) the encoded message itself without doubt for Neisseria gonorrhoeae survival (Huang (mRNA function). Secondly, tmRNA occurs in vivo in all et al., 2000). Foreign and arti®cial mRNAs are substrates bacteria with a precise biological function, in contrast to for trans-translation both in vitro and in vivo.InE.coli in vitro selected RNAs. Thirdly, tmRNAs are long enough cells, however, the only known endogenous target for (between 260 nucleotides for the shortest sequences and trans-translation is the mRNA encoding the Lac repressor ~430 nucleotides for the longer ones) to form an RNA core 2966 ã European Molecular Biology Organization Recognition between tmRNA and tRNAAla Fig. 1. Schematic illustration of (A) the usual `ribosome-driven' protein synthesis compared with (B) an hypothetical `tmRNA-driven' peptide bond formation. Tripartite lines are the triplets of the messenger RNA (1). RNAs that receive the amino acid during transpeptidation are either (A) a canonical tRNA or (B) tmRNA (2). A canonical tRNA (3) donates the amino acid prior to transpeptidation. The ribosome (4) is either (A) present or (B) absent. Notice that in (B), Fig. 2. (A) Native gel retardation assays between native canonical tmRNA is the mRNA and also the tRNA (1 and 2). tRNAs and tmRNA from E.coli. Labeled native tRNAAla3, but not native tRNAAsp, interacts with unlabeled tmRNA. (B) Labeled tRNAAla3 (0.5 pmol) binds tmRNA in the presence of all tRNAs from E.coli. with an intricate tertiary structure, a prerequisite for an solution. Our results suggest that the tRNA that decodes RNA that stands as a candidate for mimicking primitive the resume codon of E.coli tmRNA is recruited prior to its versions of the translation apparatus. Fourthly, tmRNA is interaction with the ribosome. not a ribosomal RNA. Thus, it could have arisen before the RNA±protein-based polypeptides synthesis machinery. As a step toward this task, we investigated whether Results tmRNA could interact speci®cally with either native or synthetic canonical tRNA(s), as well as with minimalist tRNAAla, but not tRNAAsp or tRNAGln, binds tmRNA RNA structures for aminoacylation, as microhelices, with speci®city in vitro proposed to be present when the genetic code was shaped Among all tRNAs, we reason that native tRNAAla from from an operational RNA code that related RNA E.coli has a relatively higher advantage in binding tmRNA sequences and/or structures to speci®c amino acids via a codon±anticodon interaction, since there are four (Schimmel et al., 1993). Our initial hypothesis was that alanine codons in the tmRNA ORF, including the resume canonical tRNAs or RNA microhelices might recognize codon. Monitoring the appearance of a slow-migrating tmRNA with speci®city in vitro. An initial recognition band that is largely pulled apart from a 76-nucleotide between tRNA and tmRNA could involve speci®c inter- labeled tRNA (size difference of 76 + 363 nucleotides) actions outside of the tmRNA internal ORF. Subsequently, should provide an unambiguous answer as to whether or nucleotides from the anticodon of the tRNA could not a speci®c tmRNA±tRNAAla complex forms in vitro.A trigger speci®c pairings with matching codons of the speci®c gel-retarded band is observed with labeled native tmRNA ORF, mimicking a `codon±anticodon' interaction. E.coli tRNAAla, but not with native tRNAAsp (Figure 2A). Minimalist structures for aminoacylation might also be For tRNAAla, the gel-retarded band migrates slower than capable of complex formation with tmRNA. Here, we labeled tmRNA alone (Figure 2A, left), suggesting that report that native E.coli tmRNA interacts either with the complex contains full-length tmRNA. The complex native or synthetic tRNAAla from E.coli in vitro, as well as between tmRNA and tRNAAla involves non-covalent with RNA microhelices whose sequences are derived from interactions, since the gel-retarded band disappears in tRNAAla isoacceptors. The structural basis of these speci®c the presence of 8 M urea (data not shown). With native interactions between tmRNA and aminoacylatable RNAs tRNAAsp, (one matching codon in the tmRNA ORF), there was de®ned further by chemical and enzymatic probes in are no detectable gel-retarded bands.
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