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. 2014 Mar 21;5:113. doi: 10.3389/fmicb.2014.00113

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Copyright © 2014 Giudice, Macé and Gillet.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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The cycle of trans-translation. Maturation: (1) The tmRNA primary transcript 5′-terminus is processed by the endonuclease RNAse P, while the 3′-terminus is first cleaved by endonucleases RNAses III or E then trimmed by exonucleases RNAses T and/or PH. Nucleotides in the T-loop are modified at least twice: a 5-methyluridine is catalysed by TrmA, and a pseudouridine may be catalyzed by TruB. (2) The tmRNA-SmpB complex is formed. (3) Ala-RS charges the deacyl tmRNA-SmpB with a new alanine. (4) Ala-RS is released. (5) EF-Tu•GDP and S1 bind to Ala-tmRNA^Ala-SmpB, and the complex is ready to rescue a stalled ribosome. Re-registration: (6) Pre-accommodation. The ala-tmRNA^Ala-SmpB-EF-Tu•GTP quaternary complex binds to a stalled ribosome. SmpB recognizes the vacant A-site. S1 is released. (7) SmpB simulates the codon-anticodon recognition and induces GTPase activity on EF-Tu. Ala-tmRNA^Ala-SmpB accommodates into the A-Site. EF-Tu•GDP and E-Site deacyl tRNA are released. (8) Peptidyl transfer. The nascent peptide is transferred from the P-Site tRNA to the Ala-tmRNA^Ala. The nascent peptide is elongated by one Ala. (9) Ratchet. The 30S subunit spontaneously rotates in an anticlockwise direction relative to the 50S. This ratchet-like motion brings TLD-SmpB and tRNA into hybrid states of binding (A/P and P/E respectively). (10) EF-G•GTP binds to the ribosome, stabilizing the ratchet formation and inducing a unique 12° head tilt. (11) GTP hydrolysis. TLD-SmpB and tRNA are translocated to the P- and E-sites, respectively. The tmRNA internal ORF is positioned in the A-site. (12) EF-G•GDP and non-stop mRNA release. Subsequent degradation of non-stop mRNA by RNAse R. Elongation: translation restart on the tmRNA internal ORF: (13) aa-tRNA^aa-EF-Tu•GDP ternary complex binds to the ribosome. (14) The recognition of tmRNA internal ORF codon by the aminoacyl tRNA induces GTP hydrolysis. The aa-tRNA^aa is accommodated in the A-site. EF-Tu•GDP and the E-Site deacyl tRNA are released. (15) Peptidyl transfer. The nascent peptide is transferred to the incoming aa-tmRNA^aa and is elongated by one amino-acid. (16) Ratchet. (17) EF-G•GTP binding. (18) GTP hydrolysis and translocation. (19) EF-G•GDP release. The process is repeated until the tmRNA STOP codon is reached. After the first cycle, like deacyl tRNAs, the TLD and SmpB are released from the E-site. Termination-recycling: (20) The tmRNA STOP codon is reached. (21) RF1 or RF2 recognize the STOP codon and bind to the A-site. (22) The class I release factor triggers P-site tRNA deacylation. The new peptide (if unfolded) or protein (if already folded by the CFM) carrying the tmRNA tag is released. A protease such as ClpXP recognizes the tag and degrades the potentially-hazardous product. (23) Class II release factor binds to the ribosome. (24) GTP hydrolysis induces a ratchet-like movement and rapid dissociation of class I and II release factors and E-site deacyl-tRNA. (25) RRF and EF-G•GTP binding. (26) GTP hydrolysis. RRF acts as a wedge, inducing dissociation and recycling of the large ribosomal subunit. RRF and EF-G•GDP are also released. (27) Deacyl tmRNA-SmpB and tRNA dissociate from the small ribosomal subunit. The 30S can be used for a new round of translation. tmRNA-SmpB is recycle. Abbreviations: Rnase III, endoribonuclease III; Rnase E, endoribonuclease E; Rnase T, exoribonuclease T; Rnase PH, exoribonuclease PH; Rnase P, endoribonuclease P; Y: pseudouridine; m5U, 5-methyluridine; TruB, tRNA pseudouridine synthase II; TrmA, S-adenosyl methionine-dependent rna methyltransferase; tmRNA, transfer-messenger RNA; SmpB, small protein B; tmRNA-SmpB, deacyl transfer-messenger RNA and small protein B binary complex; AlaRS, alanyl-tRNA synthetase; ala-tmRNA-SmpB, alanyl transfer-messenger RNA and small protein B binary complex; EF-Tu, elongation factor thermo unstable; GTP, guanosine-5′-triphosphate; S1, small ribosomal subunit protein 1; t-RNA deacyl transfer RNA; EF-G, elongation factor G; mRNA, non-stop mRNA; Rnase R, exoribonuclease R; aa-tRNA, amino-acyl transfer RNA; CFM, co-translational folding machinery; RF1/2, release factor 1 or 2; ClpXP, a protease complex; RF3, release factor 3; RRF, ribosome recycling factor; 50S, large ribosomal subunit; 30S, small ribosomal subunit.