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Till termination us do part

Nature volume 459, pages 4445 (07 May 2009) | Download Citation


Translation of messenger RNA into protein is a complex and intricate process involving several steps and many step-specific protein factors. But one factor — eIF5A — seems to have a hand in every step.

The process of translation is divided into three main steps: initiation, elongation and termination. Initiation involves the binding of ribosomes — the cell's protein-synthesis machinery — to a specific start site on the messenger RNA sequence. During elongation, the ribosome moves along the mRNA, translating its sequence into a chain of amino acids that are supplied by transfer RNA. Termination occurs when the ribosome and the nascent polypeptide both detach from the mRNA after reaching the end of the protein-coding region on the mRNA. In all three domains of life (bacteria, archaea and eukaryotes), specific protein factors aid each translation step. For example, two universally conserved elongation factors have been identified; their eukaryotic versions are called eEF1A and eEF2. On page 118 of this issue, Saini et al.1 report the existence of a third universal elongation factor, eIF5A, which is unique in that it also acts as an initiation factor and a termination factor.

That eIF5A is an essential protein in yeast is well established. Moreover, much is known about its physical characteristics and biological function2. But, despite spectacular advances in the structural analysis of both ribosomes in complex with translation factors and individual factors, the sequential use of eIF5A as a translation factor has not been investigated in detail. Until now, eIF5A has been assumed to be an initiation factor, because when purified it is recovered in association with the initiation factor eIF1A, and it is required for optimal results in a model assay for the initiation step called methionyl puromycin synthesis3.

Several observations set eIF5A apart from other initiation factors. For example, it is the only initiation factor that is more abundant as a free protein than when bound to ribosomes. Also, the lysine residue at position 51 is post-translationally modified to another amino acid, hypusine4 (Nɛ-(4-amino-2-hydroxybutyl)lysine), which is not found in any other protein in eukaryotes or archaea5 and which is essential for eIF5A activity6. Curiously, unique post-translational modifications of translation factors have been reported previously for only eEF1A and eEF2 (ref. 2). Finally, sequence alignment analysis2,7 indicates that eIF5A has evolved from the bacterial elongation factor EF-P and not from an initiation factor. Thus, the amino-acid sequence and function1,2,7,8 of eEF1A, eEF2 and eIF5A are universally maintained. By contrast, the amino-acid sequence and function of many of the polypeptides associated with either the eukaryotic initiation or termination step shows that they have not evolved from equivalent bacterial factors (see table for details).

Table 1: Evolutionary Relationships Between Bacterial And Eukaryotic Translation Factors

To directly probe the function of yeast eIF5A, Saini et al.1 used a wide combination of molecular biological and biochemical assays. They find that depletion or inactivation of this factor leads to an increase in both the levels of polysomes — clusters of ribosomes bound to mRNA — and the time it takes ribosomes, after the initiation step, to read the mRNA code and release the nascent polypeptide. What's more, the effects of eIF5A inactivation are similar to those of sordarin, an inhibitor of eEF2.

These observations clearly indicate that eIF5A functions during the elongation step. But why does it also stimulate the initiation3 and termination1 steps? One possibility is that eIF5A is required for ribosomes to adopt the most reactive conformation for optimally interacting with factors and aminoacyl-tRNAs that are specifically involved in initiation, elongation and termination.

Two hypothetical models9,10 — the reciprocating ratchet and the spring and ratchet — provide an account of how the mRNA and growing polypeptide chain are moved through the ribosome. According to these models, throughout the elongation step, the large and small ribosomal subunits move back and forth relative to one another, facilitating the movement of the mRNA and the growing polypeptide (peptidyl-tRNA) along the three consecutive sites on the ribosome — A (tRNA-binding), P (peptide-bond formation) and E (exit). Thus, faithful translation of the mRNA sequence into a polypeptide chain is ensured. As eIF5A also stimulates the initiation and termination steps, it is likely that this factor is bound to the ribosome while an initiator tRNA or the peptidyl-tRNA is bound to the P site, making the tRNA more reactive with an incoming aminoacyl-tRNA or termination factor at the A site.

Given that, at a relative molecular mass (Mr) of 15,000, eIF5A is much smaller than a ribosome — which has an Mr of roughly 4 million — it is unlikely that its effect on ribosome conformation can be detected experimentally. Nonetheless, data obtained through cryo-electron microscopy and three-dimensional reconstructions show11 that, when bound to the 40S subunit of ribosomes, the initiation factors eIF1 and eIF1A (both about the same size as eIF5A) dramatically change the shape of this subunit, although the factors themselves cannot be visualized. So it might be possible to similarly investigate whether eIF5A alters the shape or subunit orientation of eukaryotic ribosomes, without necessarily visualizing it.

Saini and colleagues' results do not just establish a role for eIF5A as a major player during the elongation step. In eIF5A, they also add a useful tool to the experimental tool box, which should allow high-resolution probing of the alternating states that eukaryotic ribosomes might assume in order to accurately and efficiently catalyse the various steps of translation.


  1. 1.

    , , & Nature 459, 118–121 (2009).

  2. 2.

    & In Translational Control of Gene Expression (eds Sonenberg, N., Hershey, J. W. B. & Mathews, M. B.) 33–88 (Cold Spring Harbor Press, 2000).

  3. 3.

    , & J. Biol. Chem. 251, 5551–5557 (1976).

  4. 4.

    et al. Proc. Natl Acad. Sci. USA 80, 1854–1857 (1983).

  5. 5.

    et al. J. Biol. Chem. 262, 16585–16589 (1987).

  6. 6.

    et al. J. Biol. Chem. 266, 7988–7994 (1991).

  7. 7.

    & Proc. Natl Acad. Sci. USA 95, 224–228 (1998).

  8. 8.

    , & Science 288, 1643–1647 (2000).

  9. 9.

    Nature 226, 817–820 (1970).

  10. 10.

    , 4th, , , & Structure 16, 664–672 (2008).

  11. 11.

    et al. Mol. Cell 26, 41–50 (2007).

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  1. William Merrick is in the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

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