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Gene Review

eIF-2alpha  -  eukaryotic translation Initiation Factor...

Drosophila melanogaster

Synonyms: CG9946, Dmel\CG9946, EIF-2alpha, Eif2alpha, Eukaryotic translation initiation factor 2 subunit 1, ...
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Disease relevance of eIF-2alpha


High impact information on eIF-2alpha

  • In the initiation phase of eukaryotic translation, eIF5 stimulates the hydrolysis of GTP bound to eIF2 in the 40S ribosomal pre-initiation complex, and the resultant GDP on eIF2 is replaced with GTP by the complex nucleotide exchange factor, eIF2B [2].
  • Furthermore, we demonstrated that phosphorylation of eIF2alpha is impaired in both mutants [3].
  • Eukaryotic initiation factor (eIF) 2B catalyzes a key regulatory step in the initiation of mRNA translation. eIF2B is well characterized in mammals and in yeast, although little is known about it in other eukaryotes. eIF2B is a hetropentamer which mediates the exchange of GDP for GTP on eIF2 [4].
  • Affinity-purified antibodies, raised against a synthetic peptide based on the predicted DGCN2 sequence, specifically immunoprecipitated an eIF-2alpha kinase activity and recognized an approximately 175 kDa phosphoprotein in Western blots of Drosophila embryo extracts [5].
  • Phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF-2alpha) is one of the best-characterized mechanisms for downregulating protein synthesis in mammalian cells in response to various stress conditions [5].

Biological context of eIF-2alpha

  • DGCN2 contains all of the 12 catalytic subdomains characteristic of eukaryotic Ser/Thr protein kinases and the conserved sequence of eIF-2alpha kinases in subdomain V [5].
  • In contrast, flies bearing the alanine eIF-2alpha mutant (HA) displayed a fast growth phenotype and females were significantly larger than nontransgenic control sisters [1].
  • The expression of the eIF-2alpha mutant transgenes, under the transcriptional control of the hsp70 promoter, was induced at various times during development to assess the developmental and biochemical effects [1].
  • Complementation of Deltagcn2 in yeast by dGCN2 depends on the presence of the critical regulatory phosphorylation site (serine 51) of eIF-2alpha. dGCN2 is composed of 10 exons encoding a protein of 1589 amino acids. dGCN2 mRNA is expressed throughout Drosophila development and is particularly abundant at the earliest stages of embryogenesis [6].
  • A key transcription factor for eukaryotic initiation factor-2 alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development [7].

Anatomical context of eIF-2alpha

  • When highly purified eIF-2 is used the rate of nucleotide exchange is greatly reduced by Mg2+ and this reduction is overcome by the guanine-nucleotide-exchange factor (GEF) of rabbit reticulocytes [8].

Associations of eIF-2alpha with chemical compounds

  • Flies bearing the aspartic acid eIF-2alpha mutant (HD) transgene displayed a slow growth phenotype and small body size [1].
  • Phosphorylation of the translation initiation factor eIF-2alpha downregulates protein synthesis by sequestering the guanylate exchange factor eIF-2B [1].
  • BeK does not show any significant homology in the NH(2) terminal regulatory domain, suggesting a distinct regulatory mechanism of this novel eIF-2alpha kinase [9].
  • The Mg2+ impairment of guanine nucleotide exchange is less severe when highly purified eIF-2 is incubated at a higher temperature (37 degrees C) and is not observed at any temperature if partially purified eIF-2 is used instead of the highly purified factor [8].
  • This GEF-dependent exchange is inhibited when Drosophila eIF-2 is either phosphorylated by the hemin-controlled inhibitor (HCI) of rabbit reticulocytes or treated with phosphatidylserine or a rabbit eIF-2 X phosphatidylserine complex [8].

Other interactions of eIF-2alpha

  • Furthermore, the stable complexes between wild-type DPERK and DPERK-K671R mutant were mediated through the N terminus of the proteins and exhibited an in vitro eIF2alpha kinase activity [10].
  • Heat shock effects on phosphorylation of protein synthesis initiation factor proteins eIF-4E and eIF-2 alpha in Drosophila [11].

Analytical, diagnostic and therapeutic context of eIF-2alpha


  1. Mutations at the Ser50 residue of translation factor eIF-2alpha dominantly affect developmental rate, body weight, and viability of Drosophila melanogaster. Qu, S., Perlaky, S.E., Organ, E.L., Crawford, D., Cavener, D.R. Gene Expr. (1997) [Pubmed]
  2. Conserved bipartite motifs in yeast eIF5 and eIF2Bepsilon, GTPase-activating and GDP-GTP exchange factors in translation initiation, mediate binding to their common substrate eIF2. Asano, K., Krishnamoorthy, T., Phan, L., Pavitt, G.D., Hinnebusch, A.G. EMBO J. (1999) [Pubmed]
  3. Budding yeast GCN1 binds the GI domain to activate the eIF2alpha kinase GCN2. Kubota, H., Ota, K., Sakaki, Y., Ito, T. J. Biol. Chem. (2001) [Pubmed]
  4. Characterization of the initiation factor eIF2B and its regulation in Drosophila melanogaster. Williams, D.D., Pavitt, G.D., Proud, C.G. J. Biol. Chem. (2001) [Pubmed]
  5. Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2alpha (eIF-2alpha) kinase from Drosophila melanogaster. Homology To yeast GCN2 protein kinase. Santoyo, J., Alcalde, J., Méndez, R., Pulido, D., de Haro, C. J. Biol. Chem. (1997) [Pubmed]
  6. Isolation of the gene encoding the Drosophila melanogaster homolog of the Saccharomyces cerevisiae GCN2 eIF-2alpha kinase. Olsen, D.S., Jordan, B., Chen, D., Wek, R.C., Cavener, D.R. Genetics (1998) [Pubmed]
  7. A key transcription factor for eukaryotic initiation factor-2 alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development. Efiok, B.J., Chiorini, J.A., Safer, B. J. Biol. Chem. (1994) [Pubmed]
  8. Protein synthesis in Drosophila melanogaster embryos. Two mechanisms for guanine nucleotide exchange on eukaryotic initiation factor 2. Mateu, M.G., Sierra, J.M. Eur. J. Biochem. (1987) [Pubmed]
  9. Cloning and characterization of an eukaryotic initiation factor-2alpha kinase from the silkworm, Bombyx mori. Prasad, M.D., Han, S.J., Nagaraju, J., Lee, W.J., Brey, P.T. Biochim. Biophys. Acta (2003) [Pubmed]
  10. Functional characterization of Drosophila melanogaster PERK eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Pomar, N., Berlanga, J.J., Campuzano, S., Hernández, G., Elías, M., de Haro, C. Eur. J. Biochem. (2003) [Pubmed]
  11. Heat shock effects on phosphorylation of protein synthesis initiation factor proteins eIF-4E and eIF-2 alpha in Drosophila. Duncan, R.F., Cavener, D.R., Qu, S. Biochemistry (1995) [Pubmed]
  12. The 90-kilodalton peptide of the heme-regulated eIF-2 alpha kinase has sequence similarity with the 90-kilodalton heat shock protein. Rose, D.W., Wettenhall, R.E., Kudlicki, W., Kramer, G., Hardesty, B. Biochemistry (1987) [Pubmed]
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