eukaryotic initiation factor 4a


Summary: A component of eukaryotic initiation factor 4F that as an RNA helicase involved in unwinding the secondary structure of the 5' UNTRANSLATED REGION of MRNA. The unwinding facilitates the binding of the 40S ribosomal subunit.

Top Publications

  1. Oguro A, Ohtsu T, Svitkin Y, Sonenberg N, Nakamura Y. RNA aptamers to initiation factor 4A helicase hinder cap-dependent translation by blocking ATP hydrolysis. RNA. 2003;9:394-407 pubmed
  2. Yang H, Jansen A, Komar A, Zheng X, Merrick W, Costes S, et al. The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol Cell Biol. 2003;23:26-37 pubmed
    ..Pdcd4 binding to eIF4A is linked to its transformation-suppressing activity, as Pdcd4-eIF4A binding and consequent inhibition of translation are required for Pdcd4 transrepression of AP-1. ..
  3. Ferraiuolo M, Lee C, Ler L, Hsu J, Costa Mattioli M, Luo M, et al. A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in nonsense-mediated decay. Proc Natl Acad Sci U S A. 2004;101:4118-23 pubmed
    ..The presence of a PTC upstream from the EJC elicits NMD. Eukaryotic initiation factor 4A (eIF4A) III is a nuclear protein that interacts physically or functionally with translation ..
  4. Lindqvist L, Oberer M, Reibarkh M, Cencic R, Bordeleau M, Vogt E, et al. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE. 2008;3:e1583 pubmed publisher
    ..Our results provide an understanding into how selective targeting of RNA helicases for pharmacological intervention can be achieved. ..
  5. Rogers G, Richter N, Lima W, Merrick W. Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. J Biol Chem. 2001;276:30914-22 pubmed
    ..A simple model of how eIF4B or eIF4H affects the duplex unwinding mechanism of eIF4A is proposed. ..
  6. Yang H, Cho M, Zakowicz H, Hegamyer G, Sonenberg N, Colburn N. A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol. 2004;24:3894-906 pubmed
    ..Together, these results indicate that not only binding to eIF4A but also prevention of eIF4A binding to the MA-3 domain of eIF4Gc contributes to the mechanism by which Pdcd4 inhibits translation. ..
  7. Linder P. Yeast RNA helicases of the DEAD-box family involved in translation initiation. Biol Cell. 2003;95:157-67 pubmed
    ..We discuss here our present knowledge of the function of eIF4A and Ded1p, two DEAD-box proteins required for translation in eukaryotic cells. ..
  8. Nielsen P, Trachsel H. The mouse protein synthesis initiation factor 4A gene family includes two related functional genes which are differentially expressed. EMBO J. 1988;7:2097-105 pubmed
    ..These data suggest that the relative efficiency of protein synthesis initiation for different mRNAs, as reflected by discrimination in messenger 5'-terminal cap recognition and binding to ribosomes, varies in different tissues. ..
  9. Dorrello N, Peschiaroli A, Guardavaccaro D, Colburn N, Sherman N, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314:467-71 pubmed
    ..We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth. ..

More Information


  1. Bono F, Ebert J, Lorentzen E, Conti E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell. 2006;126:713-25 pubmed
    ..Comparison with the structure of the eIF4AIII-Btz subcomplex that we have also determined reveals that large conformational changes are required upon EJC assembly and disassembly. ..
  2. Cordin O, Tanner N, Doère M, Linder P, Banroques J. The newly discovered Q motif of DEAD-box RNA helicases regulates RNA-binding and helicase activity. EMBO J. 2004;23:2478-87 pubmed
    ..We find that the Q motif not only regulates ATP binding and hydrolysis but also regulates the affinity of the protein for RNA substrates and ultimately the helicase activity. ..
  3. Bordeleau M, Cencic R, Lindqvist L, Oberer M, Northcote P, Wagner G, et al. RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation. Chem Biol. 2006;13:1287-95 pubmed
    b>Eukaryotic initiation factor 4A (eIF4A) is a member of the DEAD-box family of putative RNA helicases whose members are involved in many aspects of RNA metabolism...
  4. Tanner N, Cordin O, Banroques J, Doère M, Linder P. The Q motif: a newly identified motif in DEAD box helicases may regulate ATP binding and hydrolysis. Mol Cell. 2003;11:127-38 pubmed
    ..These results are consistent with computer studies of the solved crystal structures. ..
  5. Wang H, Iacoangeli A, Popp S, Muslimov I, Imataka H, Sonenberg N, et al. Dendritic BC1 RNA: functional role in regulation of translation initiation. J Neurosci. 2002;22:10232-41 pubmed
    ..The results suggest a functional role of BC1 RNA as a mediator of translational control in local protein synthesis in nerve cells. ..
  6. Bordeleau M, Matthews J, Wojnar J, Lindqvist L, Novac O, Jankowsky E, et al. Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation. Proc Natl Acad Sci U S A. 2005;102:10460-5 pubmed
    ..Our results suggest that proper control of eIF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEAD-box RNA helicases with small molecules. ..
  7. Ballut L, Marchadier B, Baguet A, Tomasetto C, Seraphin B, Le Hir H. The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity. Nat Struct Mol Biol. 2005;12:861-9 pubmed
    ..We elucidate the modalities of EJC binding to RNA and provide the first example of how cellular machineries may use RNA helicases to clamp several proteins onto RNA in stable and sequence-independent manners. ..
  8. Shibuya T, Tange T, Stroupe M, Moore M. Mutational analysis of human eIF4AIII identifies regions necessary for exon junction complex formation and nonsense-mediated mRNA decay. RNA. 2006;12:360-74 pubmed
    ..Implications of these findings are discussed in the context of other recent results and a new structural model for human eIF4AIII based on the known crystal structure of Saccharomyces cerevisiae eIF4AI. ..
  9. Shibuya T, Tange T, Sonenberg N, Moore M. eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat Struct Mol Biol. 2004;11:346-51 pubmed
    ..Finally, a model is proposed by which eIF4AIII represents a new functional class of DExH/D box proteins that act as RNA clamps or 'place holders' for the sequence-independent attachment of additional factors to RNAs. ..
  10. Korneeva N, First E, Benoit C, Rhoads R. Interaction between the NH2-terminal domain of eIF4A and the central domain of eIF4G modulates RNA-stimulated ATPase activity. J Biol Chem. 2005;280:1872-81 pubmed
    ..Both cp(C3) and cp(C2) directly interact with the NH(2)-terminal domain of eIF4A, which possesses conserved ATP- and oligonucleotide-binding motifs, but not with the COOH-terminal domain. ..
  11. Chan C, Dostie J, Diem M, Feng W, Mann M, Rappsilber J, et al. eIF4A3 is a novel component of the exon junction complex. RNA. 2004;10:200-9 pubmed
    ..Using monoclonal antibodies, we show that eIF4A3 is found in the nucleus whereas eIF4A1 and eIF4A2 are found in the cytoplasm. Thus, eIF4A3 likely provides a splicing-dependent influence on the translation of mRNAs. ..
  12. Low W, Dang Y, Schneider Poetsch T, Shi Z, Choi N, Merrick W, et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol Cell. 2005;20:709-22 pubmed
    ..These results suggest that PatA will be a valuable molecular probe for future studies of eukaryotic translation initiation and may serve as a lead compound for the development of anticancer agents. ..
  13. Bordeleau M, Mori A, Oberer M, Lindqvist L, Chard L, Higa T, et al. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat Chem Biol. 2006;2:213-20 pubmed
    ..Our study demonstrates the feasibility of selectively targeting members of the DEAD-box helicase family with small-molecule inhibitors. ..
  14. Lin D, Pestova T, Hellen C, Tiedge H. Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol Cell Biol. 2008;28:3008-19 pubmed publisher
    ..Here we identify the catalytic activity of eukaryotic initiation factor 4A (eIF4A), an ATP-dependent RNA helicase, as a target of BC1-mediated translational control...
  15. Eberle J, Fecker L, Bittner J, Orfanos C, Geilen C. Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1. Br J Cancer. 2002;86:1957-62 pubmed
    ..Translation initiation factor eIF-4A1 contributes to the control of melanoma cell proliferation and may be taken into consideration when scheduling new therapeutic approaches targeting the translational control. ..
  16. Coppolecchia R, Buser P, Stotz A, Linder P. A new yeast translation initiation factor suppresses a mutation in the eIF-4A RNA helicase. EMBO J. 1993;12:4005-11 pubmed
    ..The Stm1 protein has potential RNP1 and RNP2 motifs characteristic for RNA-binding proteins. The protein also contains six highly conserved direct repeats of 21-26 amino acids and one partial repeat. ..
  17. Holzmann K, Gerner C, Pöltl A, Schafer R, Obrist P, Ensinger C, et al. A human common nuclear matrix protein homologous to eukaryotic translation initiation factor 4A. Biochem Biophys Res Commun. 2000;267:339-44 pubmed
    ..Experiments with tagged deletion mutants indicated that the N-terminal amino acid sequence is necessary for nuclear localization. A putative role of hNMP 265 in pre-mRNA processing is discussed. ..
  18. Pause A, Sonenberg N. Mutational analysis of a DEAD box RNA helicase: the mammalian translation initiation factor eIF-4A. EMBO J. 1992;11:2643-54 pubmed
    ..Our results suggest that the highly conserved regions in the DEAD box family are critical for RNA helicase activity. ..
  19. Palacios I, Gatfield D, St Johnston D, Izaurralde E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature. 2004;427:753-7 pubmed
    ..Thus, we have identified eIF4AIII and Barentsz as components of a conserved protein complex that is essential for mRNA localization in flies and NMD in mammals. ..
  20. Svitkin Y, Pause A, Haghighat A, Pyronnet S, Witherell G, Belsham G, et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure. RNA. 2001;7:382-94 pubmed
    ..Finally, the elF4A mutant forms a more stable complex with elF4G, as compared to the wild-type elF4A, thus explaining the mechanism by which substoichiometric amounts of mutant elF4A inhibit translation. ..
  21. Low W, Dang Y, Bhat S, Romo D, Liu J. Substrate-dependent targeting of eukaryotic translation initiation factor 4A by pateamine A: negation of domain-linker regulation of activity. Chem Biol. 2007;14:715-27 pubmed
    ..Furthermore, binding of PatA is dependent on substrate (RNA and ATP) binding, and the increased activity upon PatA binding is caused by relief of a negative regulatory function of the eIF4A unique domain linker. ..
  22. Oguro A, Ohtsu T, Nakamura Y. An aptamer-based biosensor for mammalian initiation factor eukaryotic initiation factor 4A. Anal Biochem. 2009;388:102-7 pubmed publisher
    ..Here we demonstrate that an RNA aptamer selected against eukaryotic initiation factor 4A (eIF4A) serves as an efficient biosensor...
  23. Andersen C, Ballut L, Johansen J, Chamieh H, Nielsen K, Oliveira C, et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science. 2006;313:1968-72 pubmed
    ..The MAGOH and Y14 subunits lock eIF4AIII in a prehydrolysis state, and activation of the ATPase probably requires only modest conformational changes in eIF4AIII motif I. ..
  24. Low W, Dang Y, Schneider Poetsch T, Shi Z, Choi N, Rzasa R, et al. Isolation and identification of eukaryotic initiation factor 4A as a molecular target for the marine natural product Pateamine A. Methods Enzymol. 2007;431:303-24 pubmed
    ..We have attempted to present the methodology as a general technique for the identification of protein targets for small molecules including natural products. ..
  25. Yoder Hill J, Pause A, Sonenberg N, Merrick W. The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF-4A. J Biol Chem. 1993;268:5566-73 pubmed
  26. Li Q, Imataka H, Morino S, Rogers G, Richter Cook N, Merrick W, et al. Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII. Mol Cell Biol. 1999;19:7336-46 pubmed
    b>Eukaryotic initiation factor 4A (eIF4A) is an RNA-dependent ATPase and ATP-dependent RNA helicase that is thought to melt the 5' proximal secondary structure of eukaryotic mRNAs to facilitate attachment of the 40S ribosomal subunit...
  27. Oberer M, Marintchev A, Wagner G. Structural basis for the enhancement of eIF4A helicase activity by eIF4G. Genes Dev. 2005;19:2212-23 pubmed
    ..This model can explain the cooperativity between all binding partners of eIF4A (eIF4G, RNA, ATP) and stimulation of eIF4A activity in the eIF4F complex. ..
  28. Buhler M, Steiner S, Mohn F, Paillusson A, Mühlemann O. EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3' UTR length. Nat Struct Mol Biol. 2006;13:462-4 pubmed
    ..As in yeast, this exon junction complex-independent NMD of Ig-mu mRNAs depends on the distance between the termination codon and the poly(A) tail and suggests an evolutionarily conserved mode of PTC recognition. ..
  29. Eberle J, Krasagakis K, Orfanos C. Translation initiation factor eIF-4A1 mRNA is consistently overexpressed in human melanoma cells in vitro. Int J Cancer. 1997;71:396-401 pubmed
    ..Cultures of congenital melanocytic nevi exhibited intermediate expression of eIF-4A1. Thus, eIF-4A1 overexpression seems to be an important feature of melanoma cells and might contribute to their malignant transformation. ..
  30. Imataka H, Sonenberg N. Human eukaryotic translation initiation factor 4G (eIF4G) possesses two separate and independent binding sites for eIF4A. Mol Cell Biol. 1997;17:6940-7 pubmed
    ..In contrast to eIF4G, human p97, a translation inhibitor with homology to eIF4G, binds eIF4A only through the amino-terminal proximal region, which is homologous to the middle domain of eIF4G. ..
  31. Tange T, Shibuya T, Jurica M, Moore M. Biochemical analysis of the EJC reveals two new factors and a stable tetrameric protein core. RNA. 2005;11:1869-83 pubmed
    ..Using the same methodology, we further identified what appears to be the minimal stable EJC core, a heterotetrameric complex consisting of eIF4AIII, Magoh, Y14, and MLN51. ..
  32. Singh G, Chavan H, Dey C. Proteomic analysis of miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A). Int J Antimicrob Agents. 2008;31:584-6 pubmed publisher
  33. Lee H, Choe J, Chi S, Kim Y. Exon junction complex enhances translation of spliced mRNAs at multiple steps. Biochem Biophys Res Commun. 2009;384:334-40 pubmed publisher
    ..These results suggest that EJC modulates translation of spliced mRNA at multiple steps. ..
  34. Quinn C, Wiles A, El Shanawany T, Catchpole I, Alnadaf T, Ford M, et al. The human eukaryotic initiation factor 4AI gene (EIF4A1) contains multiple regulatory elements that direct high-level reporter gene expression in mammalian cell lines. Genomics. 1999;62:468-76 pubmed
    The gene encoding human eukaryotic initiation factor 4A (EIF4A1) is located on chromosome 17p13, 667 bp upstream from the gene encoding the macrophage endosomal protein CD68...
  35. Fukao A, Sasano Y, Imataka H, Inoue K, Sakamoto H, Sonenberg N, et al. The ELAV protein HuD stimulates cap-dependent translation in a Poly(A)- and eIF4A-dependent manner. Mol Cell. 2009;36:1007-17 pubmed publisher
    ..This example of cap-dependent translational regulation might explain at least in part how HuD triggers the induction of neuronal differentiation. ..
  36. Buchwald G, Ebert J, Basquin C, Sauliere J, Jayachandran U, Bono F, et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc Natl Acad Sci U S A. 2010;107:10050-5 pubmed publisher
    ..The binding mode to eIF4AIII identifies a surface hot spot that is used by different DEAD-box proteins to recruit their regulators. ..
  37. Suzuki C, Garces R, Edmonds K, Hiller S, Hyberts S, Marintchev A, et al. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc Natl Acad Sci U S A. 2008;105:3274-9 pubmed publisher
    Programmed Cell Death 4 (PDCD4) is a protein known to bind eukaryotic initiation factor 4A (eIF4A), inhibit translation initiation, and act as a tumor suppressor...
  38. Rozovsky N, Butterworth A, Moore M. Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. RNA. 2008;14:2136-48 pubmed publisher
    ..Our findings mirror and expand on recent biochemical and structural data regarding the interaction of eIF4AI's close relative eIF4AIII with its accessory protein MLN51. ..
  39. Laronde Leblanc N, Santhanam A, Baker A, Wlodawer A, Colburn N. Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol. 2007;27:147-56 pubmed
    ..Finally, our structural analysis reveals MA3 domains to be a novel subfamily of VHS domains. ..
  40. Lee A, Kim N, Park S. All trans-retinoic acid (ATRA) elevated eukaryotic translation initiation factor 4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginous epidermis. Pigment Cell Res. 2004;17:659-67 pubmed
    ..Therefore, eIF4A1 mRNA may be an important gene related to ATRA effects, although further studies are required. ..
  41. Tacken M, Thomas A, Peeters B, Rottier P, Boot H. VP1, the RNA-dependent RNA polymerase and genome-linked protein of infectious bursal disease virus, interacts with the carboxy-terminal domain of translational eukaryotic initiation factor 4AII. Arch Virol. 2004;149:2245-60 pubmed
    ..The biological relevance of the potential VP1-eIF4AII interaction is discussed. ..
  42. Hutchins A, Roberts G, Lloyd C, Doonan J. In vivo interaction between CDKA and eIF4A: a possible mechanism linking translation and cell proliferation. FEBS Lett. 2004;556:91-4 pubmed
    ..The CDKA-eIF4A complex contains kinase activity that is sensitive to the CDK-specific inhibitor roscovitine. This interaction points to a possible molecular mechanism linking cell proliferation with translational control. ..
  43. Henis Korenblit S, Strumpf N, Goldstaub D, Kimchi A. A novel form of DAP5 protein accumulates in apoptotic cells as a result of caspase cleavage and internal ribosome entry site-mediated translation. Mol Cell Biol. 2000;20:496-506 pubmed
  44. Chakrabarti R, Chakrabarti D, Souba W, Schuster S. Interaction of the eucaryotic peptide chain initiation factor eIF-4A with the specific elements at the 5'-untranslated sequence of human asparagine synthetase mRNA. J Biol Chem. 1993;268:1298-303 pubmed
    ..This 46-kDa protein factor is most likely to be the eucaryotic peptide chain initiation factor eIF-4A as determined by immunoprecipitation experiments using a monoclonal antibody raised against reticulocyte eIF-4A. ..
  45. Blum S, Schmid S, Pause A, Buser P, Linder P, Sonenberg N, et al. ATP hydrolysis by initiation factor 4A is required for translation initiation in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1992;89:7664-8 pubmed
  46. Barhoumi M, Tanner N, Banroques J, Linder P, Guizani I. Leishmania infantum LeIF protein is an ATP-dependent RNA helicase and an eIF4A-like factor that inhibits translation in yeast. FEBS J. 2006;273:5086-100 pubmed
    ..Furthermore, the 25 amino terminal residues were shown to enhance the ability of LeIF to interfere with the translation machinery in yeast. ..
  47. Li J, Li W, Gelbart W. A genetic screen for maternal-effect suppressors of decapentaplegic identifies the eukaryotic translation initiation factor 4A in Drosophila. Genetics. 2005;171:1629-41 pubmed
    ..This result provides an intriguing link between a component of the translation machinery and Dpp signaling. ..
  48. Gharbi S, Garzón B, Gayarre J, Timms J, Perez Sala D. Study of protein targets for covalent modification by the antitumoral and anti-inflammatory prostaglandin PGA1: focus on vimentin. J Mass Spectrom. 2007;42:1474-84 pubmed
    ..Our observations indicate that cysteine 328 is the main site for PGA(1) addition. These results may contribute to a better understanding of the mechanism of action of PGA(1) and the potential of cyPG-based therapeutic strategies. ..
  49. Le Hir H, Andersen G. Structural insights into the exon junction complex. Curr Opin Struct Biol. 2008;18:112-9 pubmed publisher
  50. Gastens M, Fischer H. Toxoplasma gondii eukaryotic translation initiation factor 4A associated with tachyzoite virulence is down-regulated in the bradyzoite stage. Int J Parasitol. 2002;32:1225-34 pubmed
    ..The down-regulation of eIF4A in attenuated T. gondii parasites and in the bradyzoite stage implies a role in tuning of the homeostasis of protein biosynthesis. ..
  51. Stassinopoulos I, Belsham G. A novel protein-RNA binding assay: functional interactions of the foot-and-mouth disease virus internal ribosome entry site with cellular proteins. RNA. 2001;7:114-22 pubmed
    ..Poly (rC) binding protein-2 bound to the central domain of the FMDV IRES, but depletion of RRL with this IRES domain had no effect on FMDV IRES-directed translation initiation. ..
  52. Korneeva N, Lamphear B, Hennigan F, Merrick W, Rhoads R. Characterization of the two eIF4A-binding sites on human eIF4G-1. J Biol Chem. 2001;276:2872-9 pubmed
    ..2 x 10(5) m(-1) s(-1), 2.1 x 10(-3) s(-1), and 17 nm for the central site and 5.1 x 10(3) m(-1) s(-1), 1.7 x 10(-3) s(-1), and 330 nm for the COOH-terminal site. ..
  53. Sato H, Maquat L. Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta. Genes Dev. 2009;23:2537-50 pubmed publisher
    ..Our studies uncover a previously unappreciated role for IMPbeta and a novel paradigm for how newly synthesized messenger ribonucleoproteins (mRNPs) are matured. ..