E2AK1_MOUSE
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 03-AUG-2022, entry version 174.
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 FUNCTION, TISSUE SPECIFICITY, ACTIVITY REGULATION, AND DISRUPTION
RP PHENOTYPE.
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).
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). Similarly, in hepatocytes, involved in
CC heme-mediated translational control of CYP2B and CYP3A and possibly
CC other hepatic P450 cytochromes (PubMed:20071449). May also regulate
CC endoplasmic reticulum (ER) stress during acute heme-deficient
CC conditions (PubMed:20071449). Also activates the ISR in response to
CC mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is
CC activated upon binding to the processed form of DELE1 (S-DELE1),
CC thereby promoting the ATF4-mediated reprogramming (By similarity).
CC {ECO:0000250|UniProtKB:Q9BQI3, ECO:0000269|PubMed:11050009,
CC ECO:0000269|PubMed:11726526, ECO:0000269|PubMed:12767237,
CC ECO:0000269|PubMed:15931390, ECO:0000269|PubMed:16893190,
CC 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, PubMed:20071449). Inhibited by heme:
CC in presence of heme, forms a disulfide-linked inactive homodimer (By
CC similarity). Heme depletion relieves inhibition and stimulates kinase
CC activity by autophosphorylation (PubMed:12767237, PubMed:14752110,
CC PubMed:20071449). Inhibited by the heme metabolites biliverdin and
CC bilirubin (PubMed:16893190). Induced by oxidative stress generated by
CC arsenite treatment (PubMed:12767237). Binding of nitric oxide (NO) to
CC the heme iron in the N-terminal heme-binding domain activates the
CC kinase activity, while binding of carbon monoxide (CO) suppresses
CC kinase activity (PubMed:14752110). Protein kinase activity is also
CC activated upon binding to the processed form of DELE1 (S-DELE1):
CC interaction with S-DELE1 takes place in response to mitochondrial
CC stress and triggers the integrated stress response (ISR) (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 ECO:0000269|PubMed:20071449}.
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 to the processed form of DELE1 (S-DELE1) in
CC response to mitochondrial stress, leading to activate its protein
CC kinase activity and trigger the integrated stress response (ISR) (By
CC 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 PubMed:20071449). {ECO:0000269|PubMed:11689689,
CC ECO:0000269|PubMed:17932563, ECO:0000269|PubMed:20071449}.
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). In
CC hepatocytes, cytochromes P450 CYP2B6 and CYP3A induction by
CC phenobarbital is not impaired in response to acute heme depletion and
CC CYP2B6 and CYP3A proteins continue to accumulate to supranormal levels,
CC irrespective of the hepatic heme pool status (PubMed:20071449). These
CC cells also exhibit a weak, albeit significant, elevation of the basal
CC ER-stress as reflected by elevated levels of autophosphorylated
CC EIF2AK3/PERK and EIF2AK4/GCN2, the ER-stress related chaperones HSPA5
CC and HSP90B1, and total hepatic protein ubiquitination
CC (PubMed:20071449). {ECO:0000269|PubMed:11726526,
CC ECO:0000269|PubMed:17932563, 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 -!- SEQUENCE CAUTION:
CC Sequence=BAD32438.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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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; Q9Z2R9; -.
DR PRIDE; Q9Z2R9; -.
DR ProteomicsDB; 277662; -.
DR Antibodypedia; 11579; 312 antibodies from 30 providers.
DR DNASU; 15467; -.
DR Ensembl; ENSMUST00000100487; ENSMUSP00000098056; ENSMUSG00000029613.
DR GeneID; 15467; -.
DR KEGG; mmu:15467; -.
DR UCSC; uc029vqe.1; mouse.
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; 64059at2759; -.
DR PhylomeDB; Q9Z2R9; -.
DR TreeFam; TF329383; -.
DR BioGRID-ORCS; 15467; 2 hits in 54 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 250 other tissues.
DR Genevisible; Q9Z2R9; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
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:0055072; P:iron ion homeostasis; IMP:MGI.
DR GO; GO:0030225; P:macrophage differentiation; 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 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 Pfam; PF00069; Pkinase; 2.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
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
