InterPro domain: IPR001884

Eukaryotic eIF-5A was initially thought to function as a translation initiation factor, based on its ability to stimulate methionyl-puromycin synthesis. However, subsequent work revealed a role for eIF5A in translation elongation [ 1 , 2 ]. Depletion or inactivation of eIF-5A in the yeast Saccharomyces cerevisiae (Baker's yeast) resulted in the accumulation of polysomes and an increase in ribosomal transit times. Addition of recombinant eIF-5A from yeast, but not a derivative lacking hypusine, enhanced the rate of tripeptide synthesis in vitro. Moreover, inactivation of eIF-5A mimicked the effects of the eEF2 inhibitor sordarin, indicating that eIF-5A might function together with eEF2 to promote ribosomal translocation. Finally, it was shown that eIF5A is specifically required to promote peptide-bond formation between consecutive proline residues. It has been proposed to stimulate the peptidyl-transferase activity of the ribosome and facilitate the reactivity of poor substrates like proline [ 3 ].

eIF-5A is a cofactor for the Rev and Rex transactivator proteins of human immunodeficiency virus-1 and T-cell leukaemia virus I, respectively [ 4 , 5 , 6 ]. IF-5A is the sole protein in eukaryotes and archaea to contain the unusual amino acid hypusine (Ne-(4-amino-2-hydroxybutyl)lysine) that is an absolute functional requirement. The first step in the post-translational modification of lysine to hypusine is catalyzed by the enzyme deoxyhypusine synthase, the structure of which has been reported [ 7 ].

The archaeal IF-5A proteins have not been studied as comprehensively as their eukaryotic homologues, though the crystal structure of the Pyrobaculum aerophilum protein has been determined. Unmodified P. aerophilum IF-5A is found to be a beta structure with two domains and three separate hydrophobic cores. The lysine (Lys42) that is post-translationally modified by deoxyhypusine synthase is found at one end of the IF-5A molecule in a turn between beta strands beta4 and beta5; this lysine residue is freely solvent accessible. The C-terminal domain is found to be homologous to the cold-shock protein CspA of E. coli, which has a well characterised RNA-binding fold, suggesting that IF-5A is involved in RNA binding [ 8 ].

This family also includes the Woronin body major protein Hex1, whose sequence and structure are similar to eukaryotic initiation factor 5A (eIF5A), suggesting they share a common ancestor during evolution [ 8 ].

1. Hypusine-containing protein eIF5A promotes translation elongation. Nature 459, 118-21
2. eIF5A Functions Globally in Translation Elongation and Termination. Mol. Cell 66, 194-205.e5
3. eIF5A promotes translation of polyproline motifs. Mol. Cell 51, 35-45
4. Hypusine: its post-translational formation in eukaryotic initiation factor 5A and its potential role in cellular regulation. Biofactors 4, 95-104
5. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 11, 3105-14
6. Structure of translation initiation factor 5A from Pyrobaculum aerophilum at 1.75 A resolution. Structure 6, 1207-14
7. Crystal structure of the NAD complex of human deoxyhypusine synthase: an enzyme with a ball-and-chain mechanism for blocking the active site. Structure 6, 23-32
8. A HEX-1 crystal lattice required for Woronin body function in Neurospora crassa. Nat. Struct. Biol. 10, 264-70