EIF2AK1 explained

Eukaryotic translation initiation factor 2-alpha kinase 1 is an enzyme that in humans is encoded by the EIF2AK1 gene.^{[1] [2] [3]}

Function

EIF2AK1 inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. EIF2AK1 exerts its function through the phosphorylation of EIF2S1 at 'Ser-48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Owing to this unique heme-sensing capacity, it plays a crucial role in shutting off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), it controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of the heme and globin moieties of hemoglobin. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. EIF2AK1 also act to moderate ER stress during acute heme-deficient conditions.

Enzymology

EIF2AK1 is a kinase, thus it catalyses the following reaction:

ATP + a protein = ADP + a phosphoprotein

EIF2AK1 is induced by acute heme depletion, that not only increases EIF2AK1 protein levels, but also stimulates kinase activity by autophosphorylation. Inhibited by the heme-degradation products biliverdin and bilirubin. Induced by oxidative stress generated by arsenite treatment. Binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity. cite:https://www.uniprot.org/uniprot/Q9BQI3The HRI gene is localized to 7p22 where its 3' end slightly overlaps the 3' end of the gene JTV1. The two genes are transcribed from opposite strands. Studies in rat and rabbit suggest that the HRI gene product phosphorylates the alpha subunit of eukaryotic initiation factor 2. Its kinase activity is induced by low levels of heme and inhibited by the presence of heme.^[3]

Further reading

• Hu RM, Han ZG, Song HD . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning. . Proc. Natl. Acad. Sci. U.S.A. . 97 . 17 . 9543–8 . 2000 . 10931946 . 10.1073/pnas.160270997 . 16901 . 2000PNAS...97.9543H . etal. free .
• Shao J, Grammatikakis N, Scroggins BT . Hsp90 regulates p50(cdc37) function during the biogenesis of the activeconformation of the heme-regulated eIF2 alpha kinase. . J. Biol. Chem. . 276 . 1 . 206–14 . 2001 . 11036079 . 10.1074/jbc.M007583200 . etal. free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination. . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 10.1101/gr.143000 . 310948 .
• Hwang SY, Kim MK, Kim JC . Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers. . Mol. Cells . 10 . 5 . 584–91 . 2001 . 11101152 . 10.1007/s10059-000-0584-5 . 23228958 .
• Wiemann S, Weil B, Wellenreuther R . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. . Genome Res. . 11 . 3 . 422–35 . 2001 . 11230166 . 10.1101/gr.GR1547R . 311072 . etal.
• Simpson JC, Wellenreuther R, Poustka A . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. . EMBO Rep. . 1 . 3 . 287–92 . 2001 . 11256614 . 10.1093/embo-reports/kvd058 . 1083732 . etal.
• Anand S, Pal JK . The haem-regulated eukaryotic initiation factor 2alpha kinase: a molecular indicator of lead-toxicity anaemia in rabbits. . Biotechnol. Appl. Biochem. . 36 . Pt 1 . 57–62 . 2003 . 12149123 . 10.1042/BA20020009 . 37232105 .
• Omasa T, Chen YG, Mantalaris A . Molecular cloning and sequencing of the human heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase from bone marrow culture. . DNA Seq. . 13 . 3 . 133–7 . 2003 . 12391722 . 10.1080/10425170290023428. 13466320 . etal.
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Scherer SW, Cheung J, MacDonald JR . Human chromosome 7: DNA sequence and biology. . Science . 300 . 5620 . 767–72 . 2003 . 12690205 . 2882961 . 10.1126/science.1083423 . 2003Sci...300..767S . etal.
• Rafie-Kolpin M, Han AP, Chen JJ . Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. . Biochemistry . 42 . 21 . 6536–44 . 2003 . 12767237 . 10.1021/bi034005v .
• Hillier LW, Fulton RS, Fulton LA . The DNA sequence of human chromosome 7. . Nature . 424 . 6945 . 157–64 . 2003 . 12853948 . 10.1038/nature01782 . 2003Natur.424..157H . etal. free .
• Ota T, Suzuki Y, Nishikawa T . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . etal. free .
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Wiemann S, Arlt D, Huber W . From ORFeome to biology: a functional genomics pipeline. . Genome Res. . 14 . 10B . 2136–44 . 2004 . 15489336 . 10.1101/gr.2576704 . 528930 . etal.
• Mehrle A, Rosenfelder H, Schupp I . The LIFEdb database in 2006. . Nucleic Acids Res. . 34 . Database issue . D415–8 . 2006 . 16381901 . 10.1093/nar/gkj139 . 1347501 . etal.
• Olsen JV, Blagoev B, Gnad F . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . etal. free .

Notes and References

1. Chen JJ, London IM . Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase . Trends Biochem Sci . 20 . 3 . 105–8 . May 1995 . 7709427 . 10.1016/S0968-0004(00)88975-6 .
2. Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro . DNA Res . 7 . 1 . 65–73 . Apr 2000 . 10718198 . 10.1093/dnares/7.1.65 . free .
3. Web site: Entrez Gene: EIF2AK1 eukaryotic translation initiation factor 2-alpha kinase 1.