Biology:EIF2AK1

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Eukaryotic translation initiation factor 2-alpha kinase 1 is an enzyme that in humans is encoded by the EIF2AK1 gene.

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/Q9BQI3 The 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.

Further reading

• "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. doi:10.1073/pnas.160270997. PMID 10931946. Bibcode: 2000PNAS...97.9543H. 
• "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. doi:10.1074/jbc.M007583200. PMID 11036079. 
• "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. 2001. doi:10.1101/gr.143000. PMID 11076863. 
• "Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers.". Mol. Cells 10 (5): 584–91. 2001. doi:10.1007/s10059-000-0584-5. PMID 11101152. 
• "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. doi:10.1101/gr.GR1547R. PMID 11230166. 
• "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing.". EMBO Rep. 1 (3): 287–92. 2001. doi:10.1093/embo-reports/kvd058. PMID 11256614. 
• "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. doi:10.1042/BA20020009. PMID 12149123. 
• "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. doi:10.1080/10425170290023428. PMID 12391722. 
• "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. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M. 
• "Human chromosome 7: DNA sequence and biology.". Science 300 (5620): 767–72. 2003. doi:10.1126/science.1083423. PMID 12690205. Bibcode: 2003Sci...300..767S. 
• "Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI.". Biochemistry 42 (21): 6536–44. 2003. doi:10.1021/bi034005v. PMID 12767237. 
• "The DNA sequence of human chromosome 7.". Nature 424 (6945): 157–64. 2003. doi:10.1038/nature01782. PMID 12853948. Bibcode: 2003Natur.424..157H. 
• "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. 2004. doi:10.1038/ng1285. PMID 14702039. 
• "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. 2004. doi:10.1101/gr.2596504. PMID 15489334. 
• "From ORFeome to biology: a functional genomics pipeline.". Genome Res. 14 (10B): 2136–44. 2004. doi:10.1101/gr.2576704. PMID 15489336. 
• "The LIFEdb database in 2006.". Nucleic Acids Res. 34 (Database issue): D415–8. 2006. doi:10.1093/nar/gkj139. PMID 16381901. 
• "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.". Cell 127 (3): 635–48. 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.