ID E2AK1_MOUSE Reviewed; 619 AA. AC Q9Z2R9; Q2TA96; Q69ZK8; Q8C024; Q8K123; Q9CTP5; Q9D601; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 05-APR-2011, sequence version 2. DT 27-MAR-2024, entry version 183. DE RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 1; DE EC=2.7.11.1 {ECO:0000269|PubMed:12767237, ECO:0000305|PubMed:11726526, ECO:0000305|PubMed:9822714}; DE AltName: Full=Heme-controlled repressor; DE Short=HCR; DE AltName: Full=Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase {ECO:0000303|PubMed:11560503}; DE AltName: Full=Heme-regulated inhibitor {ECO:0000303|PubMed:11726526}; DE AltName: Full=Hemin-sensitive initiation factor 2-alpha kinase {ECO:0000303|PubMed:9822714}; GN Name=Eif2ak1 {ECO:0000312|MGI:MGI:1353448}; GN Synonyms=Hri {ECO:0000303|PubMed:11726526}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF LYS-196, AND RP AUTOPHOSPHORYLATION. RC STRAIN=C57BL/6 X CBA; TISSUE=Liver; RX PubMed=9822714; DOI=10.1074/jbc.273.48.32340; RA Berlanga J.J., Herrero S., de Haro C.; RT "Characterization of the hemin-sensitive eukaryotic initiation factor RT 2alpha kinase from mouse nonerythroid cells."; RL J. Biol. Chem. 273:32340-32346(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND DISRUPTION PHENOTYPE. RC TISSUE=Erythroleukemia; RX PubMed=11726526; DOI=10.1093/emboj/20.23.6909; RA Han A.-P., Yu C., Lu L., Fujiwara Y., Browne C., Chin G., Fleming M., RA Leboulch P., Orkin S.H., Chen J.-J.; RT "Heme-regulated eIF2alpha kinase (HRI) is required for translational RT regulation and survival of erythroid precursors in iron deficiency."; RL EMBO J. 20:6909-6918(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pancreatic islet; RX PubMed=15368895; DOI=10.1093/dnares/11.3.205; RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H., RA Nagase T., Ohara O., Koga H.; RT "Prediction of the coding sequences of mouse homologues of KIAA gene: IV. RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs RT identified by screening of terminal sequences of cDNA clones randomly RT sampled from size-fractionated libraries."; RL DNA Res. 11:205-218(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Eye, and Salivary gland; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-211 AND 445-619. RC STRAIN=C57BL/6J; TISSUE=Head, Olfactory bulb, and Retina; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-196. RX PubMed=11050009; RA Crosby J.S., Chefalo P.J., Yeh I., Ying S., London I.M., Leboulch P., RA Chen J.J.; RT "Regulation of hemoglobin synthesis and proliferation of differentiating RT erythroid cells by heme-regulated eIF-2alpha kinase."; RL Blood 96:3241-3248(2000). RN [7] RP AUTOPHOSPHORYLATION, AND HEME-BINDING. RX PubMed=11560503; DOI=10.1021/bi010983s; RA Bauer B.N., Rafie-Kolpin M., Lu L., Han A., Chen J.-J.; RT "Multiple autophosphorylation is essential for the formation of the active RT and stable homodimer of heme-regulated eIF2alpha kinase."; RL Biochemistry 40:11543-11551(2001). RN [8] RP REGULATION BY HEME DEFICIENCY; HEAT SHOCK; OSMOTIC STRESS AND OXIDATIVE RP STRESS, AND TISSUE SPECIFICITY. RX PubMed=11689689; DOI=10.1128/mcb.21.23.7971-7980.2001; RA Lu L., Han A.P., Chen J.J.; RT "Translation initiation control by heme-regulated eukaryotic initiation RT factor 2alpha kinase in erythroid cells under cytoplasmic stresses."; RL Mol. Cell. Biol. 21:7971-7980(2001). RN [9] RP CATALYTIC ACTIVITY, FUNCTION, PHOSPHORYLATION AT THR-483; THR-485 AND RP THR-490, ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-196; THR-483; THR-485 RP AND THR-490. RX PubMed=12767237; DOI=10.1021/bi034005v; RA Rafie-Kolpin M., Han A.P., Chen J.J.; RT "Autophosphorylation of threonine 485 in the activation loop is essential RT for attaining eIF2alpha kinase activity of HRI."; RL Biochemistry 42:6536-6544(2003). RN [10] RP HEME-BINDING, AND ACTIVITY REGULATION. RX PubMed=14752110; DOI=10.1074/jbc.m310273200; RA Igarashi J., Sato A., Kitagawa T., Yoshimura T., Yamauchi S., Sagami I., RA Shimizu T.; RT "Activation of heme-regulated eukaryotic initiation factor 2alpha kinase by RT nitric oxide is induced by the formation of a five-coordinate NO-heme RT complex: optical absorption, electron spin resonance, and resonance raman RT spectral studies."; RL J. Biol. Chem. 279:15752-15762(2004). RN [11] RP FUNCTION. RX PubMed=15931390; DOI=10.1172/jci24141; RA Han A.P., Fleming M.D., Chen J.J.; RT "Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine RT models of erythropoietic protoporphyria and beta-thalassemia."; RL J. Clin. Invest. 115:1562-1570(2005). RN [12] RP FUNCTION, ACTIVITY REGULATION, OLIGOMERIZATION, HEME-BINDING, AND RP INDUCTION. RX PubMed=16893190; DOI=10.1021/bi060556k; RA Miksanova M., Igarashi J., Minami M., Sagami I., Yamauchi S., Kurokawa H., RA Shimizu T.; RT "Characterization of heme-regulated eIF2alpha kinase: roles of the N- RT terminal domain in the oligomeric state, heme binding, catalysis, and RT inhibition."; RL Biochemistry 45:9894-9905(2006). RN [13] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND RP DISRUPTION PHENOTYPE. RX PubMed=17932563; DOI=10.1172/jci32084; RA Liu S., Suragani R.N., Wang F., Han A., Zhao W., Andrews N.C., Chen J.J.; RT "The function of heme-regulated eIF2alpha kinase in murine iron homeostasis RT and macrophage maturation."; RL J. Clin. Invest. 117:3296-3305(2007). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [15] RP RETRACTED PAPER. RX PubMed=20071449; DOI=10.1124/mol.109.061259; RA Acharya P., Chen J.J., Correia M.A.; RT "Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha RT kinase: a protagonist of heme-mediated translational control of CYP2B RT enzymes and a modulator of basal endoplasmic reticulum stress tone."; RL Mol. Pharmacol. 77:575-592(2010). RN [16] RP RETRACTION NOTICE OF PUBMED:20071449. RX PubMed=34404736; DOI=10.1124/mol.109.061259retraction; RA Acharya P., Chen J.J., Correia M.A.; RT "Notice of Retraction: Acharya P, Chen J-J, Correia MA (2010) Hepatic heme- RT regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a RT protagonist of heme-mediated translational control of CYP2B enzymes and a RT modulator of basal endoplasmic reticulum stress tone. Mol Pharmacol RT 77(4):575-592; doi:10.1124/mol.109.061259."; RL Mol. Pharmacol. 100:65-65(2021). CC -!- FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates CC the alpha subunit of eukaryotic translation initiation factor 2 CC (EIF2S1/eIF-2-alpha) in response to various stress conditions CC (PubMed:11726526, PubMed:12767237, PubMed:16893190). Key activator of CC the integrated stress response (ISR) required for adaptation to various CC stress, such as heme deficiency, oxidative stress, osmotic shock, CC mitochondrial dysfunction and heat shock (PubMed:11726526, CC PubMed:16893190). EIF2S1/eIF-2-alpha phosphorylation in response to CC stress converts EIF2S1/eIF-2-alpha in a global protein synthesis CC inhibitor, leading to a global attenuation of cap-dependent CC translation, while concomitantly initiating the preferential CC translation of ISR-specific mRNAs, such as the transcriptional CC activator ATF4, and hence allowing ATF4-mediated reprogramming CC (PubMed:11726526, PubMed:16893190). Acts as a key sensor of heme- CC deficiency: in normal conditions, binds hemin via a cysteine thiolate CC and histidine nitrogenous coordination, leading to inhibit the protein CC kinase activity (PubMed:16893190). This binding occurs with moderate CC affinity, allowing it to sense the heme concentration within the cell: CC heme depletion relieves inhibition and stimulates kinase activity, CC activating the ISR (PubMed:16893190). Thanks to this unique heme- CC sensing capacity, plays a crucial role to shut off protein synthesis CC during acute heme-deficient conditions (PubMed:16893190). In red blood CC cells (RBCs), controls hemoglobin synthesis ensuring a coordinated CC regulation of the synthesis of its heme and globin moieties CC (PubMed:11726526, PubMed:11050009, PubMed:15931390). It thereby plays CC an essential protective role for RBC survival in anemias of iron CC deficiency (PubMed:11726526). Iron deficiency also triggers activation CC by full-length DELE1 (By similarity). Also activates the ISR in CC response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase CC activity is activated upon binding to the processed form of DELE1 (S- CC DELE1), thereby promoting the ATF4-mediated reprogramming (By CC similarity). {ECO:0000250|UniProtKB:Q9BQI3, CC ECO:0000269|PubMed:11050009, ECO:0000269|PubMed:11726526, CC ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:15931390, CC ECO:0000269|PubMed:16893190, ECO:0000269|PubMed:20071449}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:12767237, ECO:0000305|PubMed:11726526, CC ECO:0000305|PubMed:9822714}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000269|PubMed:12767237, ECO:0000305|PubMed:11726526, CC ECO:0000305|PubMed:9822714}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:12767237, CC ECO:0000305|PubMed:11726526, ECO:0000305|PubMed:9822714}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; CC Evidence={ECO:0000305|PubMed:11726526, ECO:0000305|PubMed:9822714}; CC -!- ACTIVITY REGULATION: In normal conditions, the protein kinase activity CC is inhibited; inhibition is relieved by various stress conditions CC (PubMed:12767237, PubMed:14752110). Inhibited by heme: in presence of CC heme, forms a disulfide-linked inactive homodimer (By similarity). Heme CC depletion relieves inhibition and stimulates kinase activity by CC autophosphorylation (PubMed:12767237, PubMed:14752110). Inhibited by CC the heme metabolites biliverdin and bilirubin (PubMed:16893190). CC Induced by oxidative stress generated by arsenite treatment CC (PubMed:12767237). Binding of nitric oxide (NO) to the heme iron in the CC N-terminal heme-binding domain activates the kinase activity, while CC binding of carbon monoxide (CO) suppresses kinase activity CC (PubMed:14752110). Protein kinase activity is also activated upon CC binding to DELE1 in response to various stress, triggering the CC integrated stress response (ISR): activated by full-length DELE1 in CC response to iron deficiency, while it is activated by the processed CC form of DELE1 (S-DELE1) in response to mitochondrial stress (By CC similarity). {ECO:0000250|UniProtKB:P33279, CC ECO:0000250|UniProtKB:Q9BQI3, ECO:0000269|PubMed:12767237, CC ECO:0000269|PubMed:14752110, ECO:0000269|PubMed:16893190}. CC -!- SUBUNIT: Synthesized in an inactive form that binds to the N-terminal CC domain of CDC37 (By similarity). Has to be associated with a CC multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation CC and activation by autophosphorylation. The phosphatase PPP5C modulates CC this activation (By similarity). Homodimer; homodimerizes in presence CC of heme, forming a disulfide-linked inactive homodimer (By similarity). CC Interacts with DELE1; binds both to full-length DELE1 and processed CC form of DELE1 (S-DELE1) in response to stress, leading to activate its CC protein kinase activity and trigger the integrated stress response CC (ISR) (By similarity). {ECO:0000250|UniProtKB:P33279, CC ECO:0000250|UniProtKB:Q9BQI3}. CC -!- INTERACTION: CC Q9Z2R9; Q6ZWX6: Eif2s1; NbExp=6; IntAct=EBI-642878, EBI-1202234; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11050009, CC ECO:0000269|PubMed:17932563}. CC -!- TISSUE SPECIFICITY: Expressed predominantly in erythroid cells, mature CC reticulocytes, as well as fetal liver nucleated erythroid cells CC (PubMed:11689689). At much lower levels, expressed in hepatocytes and CC bone marrow-derived macrophages (at protein level) (PubMed:17932563). CC {ECO:0000269|PubMed:11689689, ECO:0000269|PubMed:17932563}. CC -!- DEVELOPMENTAL STAGE: Highly expressed in fetal liver erythroid CC precursor cells at 14.5 dpc (at protein level). CC {ECO:0000269|PubMed:17932563}. CC -!- INDUCTION: By phenobarbital. {ECO:0000269|PubMed:16893190}. CC -!- PTM: Activated by autophosphorylation; phosphorylated predominantly on CC serine and threonine residues, but also on tyrosine residues CC (PubMed:9822714, PubMed:11560503). Autophosphorylation at Thr-485 is CC required for kinase activation (PubMed:12767237). The active CC autophosphorylated form apparently is largely refractory to cellular CC heme fluctuations (PubMed:12767237). {ECO:0000269|PubMed:11560503, CC ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:9822714}. CC -!- DISRUPTION PHENOTYPE: Mice are viable and fertile without gross CC morphological abnormalities but display hyperchromic anemia in animals CC suffering from iron deficiency (PubMed:11726526). Dramatically altered CC response to diet-induced iron deficiency shifting from an adaptive CC decrease in red blood cells (RBCs) volume and intracellular hemoglobin CC content to an increased production of abnormally dense red blood cells CC (RBCs) with decreasing red cell counts (PubMed:11726526). The decrease CC in RBC number is the result of increased apoptosis of erythroid CC precursors (PubMed:11726526). Diminished levels of phosphorylated CC EIF2S1 in bone marrow-derived macrophages (BMDMs) (PubMed:17932563). CC Impaired maturation of BMDMs and blunted inflammatory response to LPS CC with a reduced cytokine production. Impaired phagocytosis of senescent CC RBCs by macrophages, resulting in a lower phagocytosis index and lower CC percentage of macrophages with ingested RBC (PubMed:17932563). CC {ECO:0000269|PubMed:11726526, ECO:0000269|PubMed:17932563, CC ECO:0000269|PubMed:20071449}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- CAUTION: Was reported, in hepatocytes, to be involved in heme-mediated CC translational control of CYP2B and CYP3A and possibly other hepatic CC P450 cytochromes. Was reported that it may also regulate endoplasmic CC reticulum (ER) stress during acute heme-deficient conditions. However, CC this paper has been retracted because of improper data manipulation, CC reuse, and analyses. {ECO:0000305|PubMed:20071449, CC ECO:0000305|PubMed:34404736}. CC -!- SEQUENCE CAUTION: CC Sequence=BAD32438.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF028808; AAC79201.1; -; mRNA. DR EMBL; AY033898; AAK55766.1; -; mRNA. DR EMBL; AK173160; BAD32438.1; ALT_INIT; mRNA. DR EMBL; BC028923; AAH28923.1; -; mRNA. DR EMBL; BC111035; AAI11036.1; -; mRNA. DR EMBL; AK014775; BAB29545.1; -; mRNA. DR EMBL; AK020887; BAB32242.1; -; mRNA. DR EMBL; AK032508; BAC27901.1; -; mRNA. DR CCDS; CCDS84994.1; -. DR RefSeq; NP_038585.2; NM_013557.2. DR AlphaFoldDB; Q9Z2R9; -. DR BioGRID; 200421; 1. DR IntAct; Q9Z2R9; 2. DR MINT; Q9Z2R9; -. DR STRING; 10090.ENSMUSP00000098056; -. DR ChEMBL; CHEMBL1938213; -. DR iPTMnet; Q9Z2R9; -. DR PhosphoSitePlus; Q9Z2R9; -. DR EPD; Q9Z2R9; -. DR PaxDb; 10090-ENSMUSP00000098056; -. DR ProteomicsDB; 277662; -. DR Antibodypedia; 11579; 347 antibodies from 30 providers. DR DNASU; 15467; -. DR Ensembl; ENSMUST00000100487.6; ENSMUSP00000098056.5; ENSMUSG00000029613.16. DR GeneID; 15467; -. DR KEGG; mmu:15467; -. DR UCSC; uc029vqe.1; mouse. DR AGR; MGI:1353448; -. DR CTD; 27102; -. DR MGI; MGI:1353448; Eif2ak1. DR VEuPathDB; HostDB:ENSMUSG00000029613; -. DR eggNOG; KOG1035; Eukaryota. DR GeneTree; ENSGT00940000157605; -. DR HOGENOM; CLU_000288_134_1_1; -. DR InParanoid; Q9Z2R9; -. DR OMA; WDWIADR; -. DR OrthoDB; 8734at2759; -. DR PhylomeDB; Q9Z2R9; -. DR TreeFam; TF329383; -. DR BioGRID-ORCS; 15467; 2 hits in 57 CRISPR screens. DR ChiTaRS; Eif2ak1; mouse. DR PRO; PR:Q9Z2R9; -. DR Proteomes; UP000000589; Chromosome 5. DR RNAct; Q9Z2R9; Protein. DR Bgee; ENSMUSG00000029613; Expressed in fetal liver hematopoietic progenitor cell and 253 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; ISS:UniProtKB. DR GO; GO:0020037; F:heme binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IMP:MGI. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0002526; P:acute inflammatory response; IMP:MGI. DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI. DR GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB. DR GO; GO:0140467; P:integrated stress response signaling; ISS:UniProtKB. DR GO; GO:0030225; P:macrophage differentiation; IMP:MGI. DR GO; GO:0060586; P:multicellular organismal-level iron ion homeostasis; IMP:MGI. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB. DR GO; GO:0046986; P:negative regulation of hemoglobin biosynthetic process; IDA:UniProtKB. DR GO; GO:0017148; P:negative regulation of translation; IEA:UniProtKB-KW. DR GO; GO:0006909; P:phagocytosis; IMP:MGI. DR GO; GO:0046777; P:protein autophosphorylation; IEP:UniProtKB. DR GO; GO:0046501; P:protoporphyrinogen IX metabolic process; IGI:MGI. DR GO; GO:0010999; P:regulation of eIF2 alpha phosphorylation by heme; IGI:MGI. DR GO; GO:0046984; P:regulation of hemoglobin biosynthetic process; IGI:MGI. DR GO; GO:0006417; P:regulation of translation; IMP:MGI. DR GO; GO:1990641; P:response to iron ion starvation; ISS:UniProtKB. DR CDD; cd14049; STKc_EIF2AK1_HRI; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR11042:SF136; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 1; 1. DR PANTHER; PTHR11042; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE EIF2-ALPHA KINASE -RELATED; 1. DR Pfam; PF00069; Pkinase; 2. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q9Z2R9; MM. PE 1: Evidence at protein level; KW ATP-binding; Cytoplasm; Disulfide bond; Kinase; Nucleotide-binding; KW Phosphoprotein; Protein synthesis inhibitor; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Transferase. FT CHAIN 1..619 FT /note="Eukaryotic translation initiation factor 2-alpha FT kinase 1" FT /id="PRO_0000085942" FT DOMAIN 167..580 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REPEAT 408..413 FT /note="HRM 1" FT REPEAT 549..554 FT /note="HRM 2" FT REGION 1..40 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 440 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 173..181 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 196 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT SITE 80 FT /note="Heme-binding" FT /evidence="ECO:0000250|UniProtKB:P33279" FT MOD_RES 283 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q63185" FT MOD_RES 483 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:12767237" FT MOD_RES 485 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:12767237" FT MOD_RES 490 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 196 FT /note="K->R: Abolishes kinase activity. Impaired hemoglobin FT synthesis and proliferation of differentiating erythroid FT cells in knockin mice." FT /evidence="ECO:0000269|PubMed:11050009, FT ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:9822714" FT MUTAGEN 483 FT /note="T->A: No effect on kinase activity." FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 483 FT /note="T->D: No effect on kinase activity." FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 485 FT /note="T->A: Abolishes kinase activity." FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 485 FT /note="T->D: Constitutively active kinase; loss of FT regulation by heme and arsenite." FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 490 FT /note="T->A: Almost complete loss of kinase activity; even FT upon arsenite treatment." FT /evidence="ECO:0000269|PubMed:12767237" FT MUTAGEN 490 FT /note="T->D: Almost complete loss of kinase activity; even FT upon arsenite treatment." FT /evidence="ECO:0000269|PubMed:12767237" FT CONFLICT 20 FT /note="A -> S (in Ref. 5; BAB32242)" FT /evidence="ECO:0000305" FT CONFLICT 71 FT /note="S -> C (in Ref. 5; BAB32242)" FT /evidence="ECO:0000305" FT CONFLICT 138..150 FT /note="DPCQDNSYMQKIR -> VSPTGCTLYDKYI (in Ref. 5; FT BAB32242)" FT /evidence="ECO:0000305" FT CONFLICT 196..197 FT /note="KK -> IE (in Ref. 5; BAB29545)" FT /evidence="ECO:0000305" FT CONFLICT 371 FT /note="E -> D (in Ref. 1; AAC79201 and 2; AAK55766)" FT /evidence="ECO:0000305" FT CONFLICT 565 FT /note="V -> A (in Ref. 4; AAH28923)" FT /evidence="ECO:0000305" SQ SEQUENCE 619 AA; 69702 MW; 39DC5FF950C92F2A CRC64; MLGGSSVDGE RDTDDDAAGA VAAPPAIDFP AEVSDPKYDE SDVPAELQVL KEPLQQPTFP FLVANQLLLV SLLEHLSHVH EPNPLHSKQV FKLLCQTFIK MGLLSSFTCS DEFSSLRLHH NRAITHLMRS AKERVRQDPC QDNSYMQKIR SREIAFEAQT SRYLNEFEEL AILGKGGYGR VYKVRNKLDG QHYAIKKILI KSATKTDCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVV QPQDRVPIQL PSLEVLSEQE GDRDQGGVKD NESSSSIVFA ELTPEKEKPF GESEVKNENN NLVSYTANLV VRNSSESESS IELQEDGLTD LSVRPVVRHQ LPLGHSSELE GNFTSTDESS EGNLNLLGQT EVRYHLMLHI QMQLCELSLW DWITERNKRS REYVDEAACP YVMASVATKI FQELVEGVFY IHNMGIVHRD LKPRNIFLHG PDQQVKIGDF GLACADIIQN ADWTNRNGKG TRTHTSRVGT CLYASPEQLE GSQYDAKSDM YSLGVILLEL FQPFGTEMER ATVLTGVRTG RIPESLSKRC PVQAKYIQLL TGRNVSQRPS ALQLLQSELF QTTGNVNLTL QMKIIEQEKE IEELKKQLSL LSQDRGLKR //