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eIF5A and EF‐P: two unique translation factors are now traveling the same road

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Translational control is extremely important in all organisms, and some of its aspects are highly conserved among all primary kingdoms, such as those related to the translation elongation step. The previously classified translation initiation factor 5A (eIF5A) and its bacterial homologue elongation factor P (EF‐P) were discovered in the late 70's and have recently been the object of many studies. eIF5A and EF‐P are the only cellular proteins that undergo hypusination and lysinylation, respectively, both of which are unique posttranslational modifications. Herein, we review all the important discoveries related to the biochemical and functional characterization of these factors, highlighting the implication of eIF5A in translation elongation instead of initiation. The findings that eIF5A and EF‐P are important for specific cellular processes and play a role in the relief of ribosome stalling caused by specific amino acid sequences, such as those containing prolines reinforce the hypothesis that these factors are involved in specialized translation. Although there are some divergences between these unique factors, recent studies have clarified that they act similarly during protein synthesis. Further studies may reveal their precise mechanism of ribosome activity modulation as well as the mRNA targets that require eIF5A and EF‐P for their proper translation. WIREs RNA 2014, 5:209–222. doi: 10.1002/wrna.1211 This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation

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Sequence analysis of the modification loop of eIF5A and its homologous proteins from Archaea and bacteria. Amino acid sequences of the modified loops of eIF5A and EF‐P proteins, which surround the target lysine residue. ClustalW2 and, subsequently, WebLogo were used to perform the alignment and create the logo, respectively. The sequences of bacteria containing or lacking the modifying enzymes used for this analysis were supported by additional files from Bailly et al.
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Posttranslational modification of eIF5A and EF‐P. This scheme depicts the hypusination pathway in Archaea and eukaryotes, in which the deoxyhypusine synthase enzyme converts the specific lysine residue of eIF5A into deoxyhypusine (eIF5A‐deoxyhypusine), using the polyamine spermidine. Deoxyhypusine hydroxylase, which is absent in Archaea, hydroxylates deoxyhypusine to form eIF5A‐hypusine. In bacteria, lysinylation begins with the formation of R‐β‐lysine, which is accomplished by 2,3‐β‐lysine aminomutase enzyme (YjeK in E. coli). The lysyl‐tRNA synthase paralog (YjeA in E. coli) transfers the R‐β‐lysine to the specific lysine residue of EF‐P, which is subsequently hydroxylated by YfcM in E. coli.
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Structural analysis and comparisons of eIF5A among different organisms. (a) 3D structures of EF‐P (PDB 3A5Z), aIF5A (PDB 2EIF), and eIF5A (PBD 3ER0). The arrows indicate the lysine residues subjected to posttranslational modification. Domains I, II, and III from EF‐P, and N‐terminal (Nt) and C‐terminal (Ct) from aIF5A and eIF5A are also indicated. (b) Multiple alignments of the amino acid sequences of eIF5A and EF‐P from the eukaryotes Mus musculus, Homo sapiens, Caenorhabditis elegans, Saccharomyces cerevisiae, and Leishmania mexicanus, Archaeas Pyrococcus abyssi and Methanococcus jannaschii and prokaryotes Thermus thermophilus, Bacillus subtilis, and Escherichia coli. The horizontal arrows for β‐strands and coils for helices showed above and below the alignments indicate the predicted secondary structure of eIF5A and EF‐P, respectively. The vertical arrow indicates the lysine residue that undergoes posttranslational modification.
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The model for the mechanism of eIF5A action on the ribosome. The ribosome stalled in the translation elongation cycles with a tRNA, peptidyl‐tRNA, and aminoacyl‐tRNA in the P and A sites, respectively (left panel). eIF5A bound to the ribosome, between the P and E sites after the release of tRNA from the E‐site, to resolve the stall event (right panel). Note that hypusine residue (white arrow) binds closely to the peptidyl‐tRNA 3′‐CAA end in the PTC to enhance the formation of the peptide bond. (Reprinted with permission from Ref . Copyright 2013 Elsevier)
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