Peptide Chain Elongation: Models of the Elongation Cycle


Three models of the ribosomal elongation cycle are used to explain the mechanism of protein synthesis on the ribosome. These are the allosteric three‐site model, the hybrid site model and the α–ε model. Recent cryoelectron microscopy analyses significantly modify the current models.

Keywords: protein synthesis; ribosome; translocation of tRNAs

Figure 1.

The allosteric three‐site model with the EF‐Tu and EF‐G cycles. The model is characterized by two features: (1) A and E sites are coupled in reciprocal fashion, i.e. an occupied E site induces a low affinity of the A site, and vice versa an occupied A site prevents the binding of a tRNA to the E site. (2) The two tRNAs on the elongating ribosome are linked to the mRNA via codon–anticodon interaction. Ts indicates the GDP/GTP exchange factor EF‐Ts.

Figure 2.

X‐ray crystal structures of the elongation factors. (a) EF‐G from Thermus thermophilus (pdb1fnm) and (b) the ternary complex Phe‐tRNA·EF‐Tu·GDPNP (pdb1ttt). (b). Molecular mimicry is seen for domains III, IV and V of EF‐G (gold ribbons in (a)) which mimic the tRNA moiety within the ternary complex (gold sticks in (b)).

Figure 3.

The hybrid site model. A tRNA passes through hybrid sites during an elongation cycle. A site binding occurs in at least two steps. First, the codon is recognized on the 30S subunit and the ternary complex is bound in the A/T site. The presence of EF‐Tu prevents peptide bond formation in this state as described for the allosteric three‐site model. After GTP cleavage and dissociation of EF‐Tu·GDP, the aa‐tRNA can now interact with the 50S A site and the tRNA rearranges to the A/A site. Peptide bond formation takes place, which is immediately followed by a spontaneous movement of the tRNA region contacting the 50S subunit. As a result the newly created peptidyl‐tRNA and deacylated tRNA are in the A/P and P/E hybrid sites, respectively. An EF‐G‐dependent translocation completes the elongation cycle. The movement of the tRNAs occurs only on the 30S side and as a consequence the deacylated tRNA is in the E site and the peptidyl‐tRNA in the P/P site.

Figure 4.

The α–ε model. The occupation of the A region is separated into two reactions, 1a and 1b, similar to the two preceding models. During the decoding process 1a, the anticodon region of the aa‐tRNA within the ternary complex interacts with the decoding centre δ leaving the ribosome in the POST state. At this time three tRNAs are bound to the ribosome. When the decoding process has recognized a cognate ternary complex, the δ centre might tightly fix the freshly established codon–anticodon interaction. This induces a conformational change of the ribosome, thus allowing the α–ε domain to come off the tRNAs at the P and E sites and shift back to the tRNAs at the A and P sites (reaction 1b). The tRNA at the E site has lost its binding site ε and falls off the ribosome, thus explaining the well‐documented reciprocal relationship between A and E sites. The next basic reaction is peptide bond formation (reaction 2) followed by the EF‐G‐dependent translocation (reaction 3), which occurs by moving the ribosomal α–ε domain together with the tRNAs and the mRNA, which remain tightly bound before, during and after the translocation reaction to the α–ε domain.

Figure 5.

tRNAs within the ribosome (a) before (PRE) and (b) after (POST) translocation, as observed by cryoelectron microscopy. The top of a transparent 70S ribosome is viewed, with the 30S ribosomal subunit in front (h, head; s, spore) and the 50S subunit at the back (L1, L1 protuberance; CP, central protuberance; St, L7/L12 stalk). If the ribosome was not transparent, the 30S head and the central protuberance of the 50S subunit would cover the tRNAs at the A and P sites almost completely. Modified from Agrawal et al..

Figure 6.

Hypothesis of the movements of the tRNAs during translocation showing the movements of the small subunit assuming that the 50S subunit (omitted) is fixed. The small subunit is seen from the top (right) and from the interface (front side, middle), therefore the A site is left and E site is right (left). The regions of the A, P and E sites are blue, red and green, respectively. (a) PRE state with tRNAs at A and P sites. (b) the small subunit rotates around a rotation axis at h27 (star) that might weaken the tight tRNA‐ribosome interactions at the tRNA elbow. (c) forward turn of the ratchet movement through the neck of the small subunit (star) guiding the tRNAs to the hybrid positions A/P and P/E, respectively. (d) back movement of the ratchet turn upon GTP hydrolysis guiding the tRNAs into the P and E sites (POST state). According to Spahn et al., , modified. For more details see text.



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Further Reading

Agrawal RK, Penczek P, Grassucci RA and Frank J (1998) Visualization of elongation factor G on the Escherichia coli 70S ribosome: the mechanism of translocation. Proceedings of the National Academy of Sciences of the USA 95: 6134–6138.

Burkhardt N, Jünemann R, Spahn CMT and Nierhaus KH (1998) Ribosomal tRNA binding sites: three‐site models of translation. Critical Reviews in Biochemistry and Molecular Biology 33: 95–149.

Clark BF and Nyborg J (1997) The ternary complex of EF‐Tu and ist role in protein biosynthesis. Current Opinion in Structural Biology 7: 110–116.

Czworkowski J and Moore PB (1996) The elongation phase of protein synthesis. Progress in Nucleic Acid Research and Molecular Biology 54: 293–332.

Nierhaus KH and Wilson DN (eds) (2004) Protein Synthesis and Ribosome Structure: Translating the Genome. Weinheim, Germany: Wiley‐VCH.

Nissen P, Kjeldgaard M, Thirup S et al. (1995) Crystal structure of the ternary complex of Phe‐tRNAPhe, EF‐Tu, and a GTP analog. Science 270: 1464–1472.

Wilson DN and Nierhaus KH (2003) The ribosome through the looking glass. Angewandte Chemie Int. Ed. 43: 3463–3486.

Wilson KS and Noller HF (1998) Molecular movement inside the translational engine. Cell 92: 337–349.

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Nierhaus, Knud H, and Wilson, Daniel N(Jan 2006) Peptide Chain Elongation: Models of the Elongation Cycle. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0003949]