EIF2AK1

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

EIF2AK1
Identifiers
Aliases	EIF2AK1, HCR, HRI, eukaryotic translation initiation factor 2 alpha kinase 1, LEMSPAD, hHRI
External IDs	OMIM: 613635; MGI: 1353448; HomoloGene: 8290; GeneCards: EIF2AK1; OMA:EIF2AK1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human) Band 7p22.1 Start 6,022,247 bp End 6,059,175 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 G2 Start 143,803,543 bp End 143,841,069 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in trabecular bone monocyte parotid gland islet of Langerhans ventricular zone bone marrow mucosa of ileum bone marrow cells stromal cell of endometrium rectum Top expressed in fetal liver hematopoietic progenitor cell secondary oocyte tibiofemoral joint maxillary prominence mandibular prominence bone marrow primary oocyte right kidney tail of embryo epithelium of stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity kinase activity protein serine/threonine kinase activity ATP binding heme binding protein homodimerization activity eukaryotic translation initiation factor 2alpha kinase activity translation initiation factor activity Cellular component cytoplasm Biological process negative regulation of translation phosphorylation regulation of hemoglobin biosynthetic process iron ion homeostasis macrophage differentiation protein phosphorylation regulation of translational initiation by eIF2 alpha phosphorylation acute inflammatory response protoporphyrinogen IX metabolic process regulation of eIF2 alpha phosphorylation by heme phagocytosis negative regulation of translational initiation by iron regulation of translation negative regulation of cell population proliferation protein autophosphorylation negative regulation of hemoglobin biosynthetic process response to iron ion starvation translational initiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 27102 15467 Ensembl ENSG00000086232 ENSMUSG00000029613 UniProt Q9BQI3 Q9Z2R9 RefSeq (mRNA) NM_014413 NM_001134335 NM_013557 RefSeq (protein) NP_001127807 NP_055228 NP_055228.2 NP_038585 Location (UCSC) Chr 7: 6.02 – 6.06 Mb Chr 5: 143.8 – 143.84 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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

• Hu RM, Han ZG, Song HD, et al. (2000). "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. Bibcode:2000PNAS...97.9543H. doi:10.1073/pnas.160270997. PMC 16901. PMID 10931946.
• Shao J, Grammatikakis N, Scroggins BT, et al. (2001). "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. doi:10.1074/jbc.M007583200. PMID 11036079.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Hwang SY, Kim MK, Kim JC (2001). "Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers". Mol. Cells. 10 (5): 584–91. doi:10.1007/s10059-000-0584-5. PMID 11101152. S2CID 23228958.
• Wiemann S, Weil B, Wellenreuther R, et al. (2001). "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. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
• Anand S, Pal JK (2003). "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. doi:10.1042/BA20020009. PMID 12149123. S2CID 37232105.
• Omasa T, Chen YG, Mantalaris A, et al. (2003). "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. doi:10.1080/10425170290023428. PMID 12391722. S2CID 13466320.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Scherer SW, Cheung J, MacDonald JR, et al. (2003). "Human chromosome 7: DNA sequence and biology". Science. 300 (5620): 767–72. Bibcode:2003Sci...300..767S. doi:10.1126/science.1083423. PMC 2882961. PMID 12690205.
• Rafie-Kolpin M, Han AP, Chen JJ (2003). "Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI". Biochemistry. 42 (21): 6536–44. doi:10.1021/bi034005v. PMID 12767237.
• Hillier LW, Fulton RS, Fulton LA, et al. (2003). "The DNA sequence of human chromosome 7". Nature. 424 (6945): 157–64. Bibcode:2003Natur.424..157H. doi:10.1038/nature01782. PMID 12853948.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.