E2AK1_HUMAN
ID E2AK1_HUMAN Reviewed; 630 AA.
AC Q9BQI3; A8K2R2; Q549K6; Q8NBW3; Q9HC02; Q9NYE0; Q9P0V6; Q9P1J5; Q9P2H8;
AC Q9UHG4;
DT 11-JUL-2001, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2003, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 1 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:32132707};
DE AltName: Full=Heme-controlled repressor;
DE Short=HCR;
DE AltName: Full=Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase {ECO:0000303|Ref.3};
DE AltName: Full=Heme-regulated inhibitor {ECO:0000303|PubMed:11101152};
DE Short=hHRI {ECO:0000303|PubMed:11101152};
DE AltName: Full=Hemin-sensitive initiation factor 2-alpha kinase {ECO:0000303|Ref.2};
GN Name=EIF2AK1 {ECO:0000312|HGNC:HGNC:24921};
GN Synonyms=HRI {ECO:0000303|PubMed:11101152},
GN KIAA1369 {ECO:0000303|PubMed:10718198}; ORFNames=PRO1362;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Hair follicle dermal papilla;
RX PubMed=11101152; DOI=10.1007/s10059-000-0584-5;
RA Hwang S.-Y., Kim M.-K., Kim J.-C.;
RT "Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha
RT kinase: down-regulated in epithelial ovarian cancers.";
RL Mol. Cells 10:584-591(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Tu Q., Yu L., Hu P.R., Fu Q., Cui Y.Y., Zhao S.Y.;
RT "Cloning and sequencing of a novel human cDNA homologous to rat hemin-
RT sensitive initiation factor 2a kinase mRNA.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Skin;
RA Cannon G., Naik S.M., Boss J.M., Caughman S.W.;
RT "Cloning of the human heme-regulated eukaryotic initiation factor 2-alpha
RT kinase from TNF-alpha stimulated dermal microvascular endothelial cells.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Hypothalamus;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W.,
RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J.,
RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z.,
RA Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis
RT and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Amygdala;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Bone marrow;
RX PubMed=12391722; DOI=10.1080/10425170290023428;
RA Omasa T., Chen Y.-G., Mantalaris A., Tsai Y.C., Wu J.H.;
RT "Molecular cloning and sequencing of the human heme-regulated eukaryotic
RT initiation factor 2 alpha (eIF-2 alpha) kinase from bone marrow culture.";
RL DNA Seq. 13:133-137(2002).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-558.
RC TISSUE=Placenta, and Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary;
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 [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 450-630, AND VARIANT ARG-558.
RC TISSUE=Fetal liver;
RA Zhang C., Yu Y., Zhang S., Wei H., Zhou G., Ouyang S., Luo L., Bi J.,
RA Liu M., He F.;
RT "Functional prediction of the coding sequences of 121 new genes deduced by
RT analysis of cDNA clones from human fetal liver.";
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP INTERACTION WITH CDC37 AND THE HSP90 COMPLEX.
RX PubMed=11036079; DOI=10.1074/jbc.m007583200;
RA Shao J., Grammatikakis N., Scroggins B.T., Uma S., Huang W., Chen J.-J.,
RA Hartson S.D., Matts R.L.;
RT "Hsp90 regulates p50(cdc37) function during the biogenesis of the active
RT conformation of the heme-regulated eIF2 alpha kinase.";
RL J. Biol. Chem. 276:206-214(2001).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [16]
RP TISSUE SPECIFICITY.
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 [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP INVOLVEMENT IN LEMSPAD, FUNCTION, VARIANT LEMSPAD VAL-448, AND
RP CHARACTERIZATION OF VARIANT LEMSPAD VAL-448.
RX PubMed=32197074; DOI=10.1016/j.ajhg.2020.02.016;
RG Undiagnosed Diseases Network;
RA Mao D., Reuter C.M., Ruzhnikov M.R.Z., Beck A.E., Farrow E.G., Emrick L.T.,
RA Rosenfeld J.A., Mackenzie K.M., Robak L., Wheeler M.T., Burrage L.C.,
RA Jain M., Liu P., Calame D., Kuery S., Sillesen M., Schmitz-Abe K.,
RA Tonduti D., Spaccini L., Iascone M., Genetti C.A., Koenig M.K., Graf M.,
RA Tran A., Alejandro M., Lee B.H., Thiffault I., Agrawal P.B.,
RA Bernstein J.A., Bellen H.J., Chao H.T.;
RT "De novo EIF2AK1 and EIF2AK2 variants are associated with developmental
RT delay, leukoencephalopathy, and neurologic decompensation.";
RL Am. J. Hum. Genet. 106:570-583(2020).
RN [19]
RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH DELE1.
RX PubMed=32132706; DOI=10.1038/s41586-020-2076-4;
RA Fessler E., Eckl E.M., Schmitt S., Mancilla I.A., Meyer-Bender M.F.,
RA Hanf M., Philippou-Massier J., Krebs S., Zischka H., Jae L.T.;
RT "A pathway coordinated by DELE1 relays mitochondrial stress to the
RT cytosol.";
RL Nature 579:433-437(2020).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND INTERACTION WITH
RP DELE1.
RX PubMed=32132707; DOI=10.1038/s41586-020-2078-2;
RA Guo X., Aviles G., Liu Y., Tian R., Unger B.A., Lin Y.T., Wiita A.P.,
RA Xu K., Correia M.A., Kampmann M.;
RT "Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI
RT pathway.";
RL Nature 579:427-432(2020).
RN [21]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-117; THR-132; LYS-134; SER-139;
RP HIS-145; SER-202; LEU-292; HIS-319 AND ARG-558.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [22]
RP VARIANT ARG-558.
RX PubMed=28501589; DOI=10.1016/j.clim.2017.05.009;
RA Sadovnick A.D., Traboulsee A.L., Zhao Y., Bernales C.Q., Encarnacion M.,
RA Ross J.P., Yee I.M., Criscuoli M.G., Vilarino-Gueell C.;
RT "Genetic modifiers of multiple sclerosis progression, severity and onset.";
RL Clin. Immunol. 180:100-105(2017).
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:32132706, PubMed:32132707). Key activator of the integrated
CC stress response (ISR) required for adaptation to various stress, such
CC as heme deficiency, oxidative stress, osmotic shock, mitochondrial
CC dysfunction and heat shock (PubMed:32132706, PubMed:32132707).
CC EIF2S1/eIF-2-alpha phosphorylation in response to stress converts
CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to
CC a global attenuation of cap-dependent translation, while concomitantly
CC initiating the preferential translation of ISR-specific mRNAs, such as
CC the transcriptional activator ATF4, and hence allowing ATF4-mediated
CC reprogramming (PubMed:32132706, PubMed:32132707). Acts as a key sensor
CC of heme-deficiency: in normal conditions, binds hemin via a cysteine
CC thiolate and histidine nitrogenous coordination, leading to inhibit the
CC protein kinase activity (By similarity). This binding occurs with
CC moderate affinity, allowing it to sense the heme concentration within
CC the cell: heme depletion relieves inhibition and stimulates kinase
CC activity, activating the ISR (By similarity). Thanks to this unique
CC heme-sensing capacity, plays a crucial role to shut off protein
CC synthesis during acute heme-deficient conditions (By similarity). In
CC red blood cells (RBCs), controls hemoglobin synthesis ensuring a
CC coordinated regulation of the synthesis of its heme and globin moieties
CC (By similarity). It thereby plays an essential protective role for RBC
CC survival in anemias of iron deficiency (By similarity). Similarly, in
CC hepatocytes, involved in heme-mediated translational control of CYP2B
CC and CYP3A and possibly other hepatic P450 cytochromes (By similarity).
CC May also regulate endoplasmic reticulum (ER) stress during acute heme-
CC deficient conditions (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
CC (PubMed:32132706, PubMed:32132707). {ECO:0000250|UniProtKB:Q9Z2R9,
CC ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707,
CC ECO:0000269|PubMed:32197074}.
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:32132707};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC Evidence={ECO:0000269|PubMed:32132707};
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:0000250|UniProtKB:Q9Z2R9};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
CC -!- ACTIVITY REGULATION: In normal conditions, the protein kinase activity
CC is inhibited; inhibition is relieved by various stress conditions (By
CC similarity). Inhibited by heme: in presence of heme, forms a disulfide-
CC linked inactive homodimer (By similarity). Heme depletion relieves
CC inhibition and stimulates kinase activity by autophosphorylation.
CC Inhibited by the heme metabolites biliverdin and bilirubin (By
CC similarity). Induced by oxidative stress generated by arsenite
CC treatment. Binding of nitric oxide (NO) to the heme iron in the N-
CC terminal heme-binding domain activates the kinase activity, while
CC binding of carbon monoxide (CO) suppresses kinase activity (By
CC similarity). Protein kinase activity is also activated upon binding to
CC the processed form of DELE1 (S-DELE1): interaction with S-DELE1 takes
CC place in response to mitochondrial stress and triggers the integrated
CC stress response (ISR) (PubMed:32132706, PubMed:32132707).
CC {ECO:0000250|UniProtKB:P33279, ECO:0000250|UniProtKB:Q9Z2R9,
CC ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3.88 uM for eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) (in absence of DELE1 and in absence of hemin)
CC {ECO:0000269|PubMed:32132707};
CC KM=1.13 uM for eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) (in presence of DELE1 and in absence of hemin)
CC {ECO:0000269|PubMed:32132707};
CC KM=71.91 uM for eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) (in absence of DELE1 and in presence of hemin)
CC {ECO:0000269|PubMed:32132707};
CC KM=6.56 uM for eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) (in presence of DELE1 and in presence of hemin)
CC {ECO:0000269|PubMed:32132707};
CC -!- SUBUNIT: Synthesized in an inactive form that binds to the N-terminal
CC domain of CDC37 (PubMed:11036079). Has to be associated with a
CC multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation
CC and activation by autophosphorylation (PubMed:11036079). The
CC phosphatase PPP5C modulates this activation (PubMed:11036079).
CC Homodimer; homodimerizes in presence of heme, forming a disulfide-
CC linked inactive homodimer (By similarity). Interacts with DELE1; binds
CC to the processed form of DELE1 (S-DELE1) in response to mitochondrial
CC stress, leading to activate its protein kinase activity and trigger the
CC integrated stress response (ISR) (PubMed:32132706, PubMed:32132707).
CC {ECO:0000250|UniProtKB:P33279, ECO:0000269|PubMed:11036079,
CC ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707}.
CC -!- INTERACTION:
CC Q9BQI3; P08238: HSP90AB1; NbExp=2; IntAct=EBI-640377, EBI-352572;
CC Q9BQI3; P11142: HSPA8; NbExp=2; IntAct=EBI-640377, EBI-351896;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9BQI3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BQI3-2; Sequence=VSP_007589;
CC -!- TISSUE SPECIFICITY: Expressed predominantly in erythroid cells
CC (PubMed:20071449). Expressed at much lower levels in hepatocytes (at
CC protein level) (PubMed:20071449). {ECO:0000269|PubMed:20071449}.
CC -!- PTM: Activated by autophosphorylation; phosphorylated predominantly on
CC serine and threonine residues, but also on tyrosine residues.
CC Autophosphorylation at Thr-488 is required for kinase activation. The
CC active autophosphorylated form apparently is largely refractory to
CC cellular heme fluctuations. {ECO:0000250|UniProtKB:Q9Z2R9}.
CC -!- DISEASE: Leukoencephalopathy, motor delay, spasticity, and dysarthria
CC syndrome (LEMSPAD) [MIM:618878]: A disorder characterized by delayed
CC motor development, speech delay with dysarthria, hypertonia,
CC progressive spasticity, hyperreflexia, and bradykinesia. Cognition is
CC normal. Patients manifest anxiety and attention deficit-hyperactivity
CC disorder. {ECO:0000269|PubMed:32197074}. Note=The disease may be caused
CC by variants affecting the gene represented in this entry.
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=AAF70289.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=AAF71057.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA92607.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF255050; AAF70289.1; ALT_FRAME; mRNA.
DR EMBL; AF100784; AAP97223.1; -; mRNA.
DR EMBL; AF181071; AAF18391.1; -; mRNA.
DR EMBL; AB037790; BAA92607.1; ALT_INIT; mRNA.
DR EMBL; AF183414; AAG09683.1; -; mRNA.
DR EMBL; AL136563; CAB66498.1; -; mRNA.
DR EMBL; AF147094; AAF66736.1; -; mRNA.
DR EMBL; AK075192; BAC11461.1; -; mRNA.
DR EMBL; AK290327; BAF83016.1; -; mRNA.
DR EMBL; AL834494; CAD39152.1; -; mRNA.
DR EMBL; CH236963; EAL23714.1; -; Genomic_DNA.
DR EMBL; CH878731; EAW55049.1; -; Genomic_DNA.
DR EMBL; BC006524; AAH06524.1; -; mRNA.
DR EMBL; AF116634; AAF71057.1; ALT_INIT; mRNA.
DR CCDS; CCDS5345.1; -. [Q9BQI3-1]
DR RefSeq; NP_001127807.1; NM_001134335.1. [Q9BQI3-2]
DR RefSeq; NP_055228.2; NM_014413.3. [Q9BQI3-1]
DR AlphaFoldDB; Q9BQI3; -.
DR SMR; Q9BQI3; -.
DR BioGRID; 118002; 21.
DR IntAct; Q9BQI3; 18.
DR STRING; 9606.ENSP00000199389; -.
DR BindingDB; Q9BQI3; -.
DR ChEMBL; CHEMBL6029; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9BQI3; -.
DR GuidetoPHARMACOLOGY; 2015; -.
DR iPTMnet; Q9BQI3; -.
DR PhosphoSitePlus; Q9BQI3; -.
DR BioMuta; EIF2AK1; -.
DR DMDM; 32172458; -.
DR EPD; Q9BQI3; -.
DR jPOST; Q9BQI3; -.
DR MassIVE; Q9BQI3; -.
DR MaxQB; Q9BQI3; -.
DR PaxDb; Q9BQI3; -.
DR PeptideAtlas; Q9BQI3; -.
DR PRIDE; Q9BQI3; -.
DR ProteomicsDB; 78682; -. [Q9BQI3-1]
DR ProteomicsDB; 78683; -. [Q9BQI3-2]
DR Antibodypedia; 11579; 312 antibodies from 30 providers.
DR DNASU; 27102; -.
DR Ensembl; ENST00000199389.11; ENSP00000199389.6; ENSG00000086232.13. [Q9BQI3-1]
DR GeneID; 27102; -.
DR KEGG; hsa:27102; -.
DR MANE-Select; ENST00000199389.11; ENSP00000199389.6; NM_014413.4; NP_055228.2.
DR UCSC; uc003spp.4; human. [Q9BQI3-1]
DR CTD; 27102; -.
DR DisGeNET; 27102; -.
DR GeneCards; EIF2AK1; -.
DR HGNC; HGNC:24921; EIF2AK1.
DR HPA; ENSG00000086232; Low tissue specificity.
DR MalaCards; EIF2AK1; -.
DR MIM; 613635; gene.
DR MIM; 618878; phenotype.
DR neXtProt; NX_Q9BQI3; -.
DR OpenTargets; ENSG00000086232; -.
DR PharmGKB; PA134919097; -.
DR VEuPathDB; HostDB:ENSG00000086232; -.
DR eggNOG; KOG1035; Eukaryota.
DR GeneTree; ENSGT00940000157605; -.
DR HOGENOM; CLU_000288_134_1_1; -.
DR InParanoid; Q9BQI3; -.
DR OMA; WDWIADR; -.
DR OrthoDB; 124090at2759; -.
DR PhylomeDB; Q9BQI3; -.
DR TreeFam; TF329383; -.
DR PathwayCommons; Q9BQI3; -.
DR Reactome; R-HSA-9648895; Response of EIF2AK1 (HRI) to heme deficiency.
DR SignaLink; Q9BQI3; -.
DR SIGNOR; Q9BQI3; -.
DR BioGRID-ORCS; 27102; 20 hits in 1113 CRISPR screens.
DR ChiTaRS; EIF2AK1; human.
DR GeneWiki; EIF2AK1; -.
DR GenomeRNAi; 27102; -.
DR Pharos; Q9BQI3; Tchem.
DR PRO; PR:Q9BQI3; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q9BQI3; protein.
DR Bgee; ENSG00000086232; Expressed in trabecular bone tissue and 198 other tissues.
DR ExpressionAtlas; Q9BQI3; baseline and differential.
DR Genevisible; Q9BQI3; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0002526; P:acute inflammatory response; IEA:Ensembl.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0140468; P:HRI-mediated signaling; IDA:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; IDA:UniProtKB.
DR GO; GO:0055072; P:iron ion homeostasis; IEA:Ensembl.
DR GO; GO:0030225; P:macrophage differentiation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0046986; P:negative regulation of hemoglobin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0045993; P:negative regulation of translational initiation by iron; NAS:UniProtKB.
DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0046501; P:protoporphyrinogen IX metabolic process; IEA:Ensembl.
DR GO; GO:0010999; P:regulation of eIF2 alpha phosphorylation by heme; IEA:Ensembl.
DR GO; GO:1990641; P:response to iron ion starvation; IDA: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 Alternative splicing; ATP-binding; Disulfide bond; Kinase;
KW Nucleotide-binding; Phosphoprotein; Protein synthesis inhibitor;
KW Reference proteome; Repeat; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..630
FT /note="Eukaryotic translation initiation factor 2-alpha
FT kinase 1"
FT /id="PRO_0000085941"
FT DOMAIN 167..583
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REPEAT 410..415
FT /note="HRM 1"
FT REPEAT 552..557
FT /note="HRM 2"
FT REGION 1..40
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 259..301
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 442
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 285
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q63185"
FT MOD_RES 486
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT MOD_RES 488
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT MOD_RES 493
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT VAR_SEQ 244
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11230166,
FT ECO:0000303|PubMed:12391722, ECO:0000303|PubMed:17974005"
FT /id="VSP_007589"
FT VARIANT 117
FT /note="R -> T (in dbSNP:rs34889754)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040466"
FT VARIANT 132
FT /note="K -> T (in dbSNP:rs34851195)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040467"
FT VARIANT 134
FT /note="R -> K (in dbSNP:rs55744865)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040468"
FT VARIANT 139
FT /note="P -> S (in dbSNP:rs55963745)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040469"
FT VARIANT 145
FT /note="R -> H (in dbSNP:rs55971369)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040470"
FT VARIANT 202
FT /note="G -> S (in a lung adenocarcinoma sample; somatic
FT mutation; dbSNP:rs1216460058)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040471"
FT VARIANT 292
FT /note="F -> L (in dbSNP:rs55982710)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040472"
FT VARIANT 319
FT /note="L -> H (in dbSNP:rs34909691)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040473"
FT VARIANT 448
FT /note="I -> V (in LEMSPAD; unknown pathological
FT significance; mildly reduced phosphorylation of eukaryotic
FT translation initiation factor 2-alpha; dbSNP:rs1583476115)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084259"
FT VARIANT 558
FT /note="K -> R (in dbSNP:rs2640)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:28501589,
FT ECO:0000269|Ref.13"
FT /id="VAR_015732"
FT CONFLICT 2
FT /note="Q -> L (in Ref. 3; AAF18391)"
FT /evidence="ECO:0000305"
FT CONFLICT 4
FT /note="G -> D (in Ref. 8; BAF83016)"
FT /evidence="ECO:0000305"
FT CONFLICT 24..32
FT /note="PPAIDFPAE -> RRHRLSRR (in Ref. 1; AAF70289)"
FT /evidence="ECO:0000305"
FT CONFLICT 137
FT /note="Q -> R (in Ref. 1; AAF70289)"
FT /evidence="ECO:0000305"
FT CONFLICT 149
FT /note="I -> T (in Ref. 8; BAF83016)"
FT /evidence="ECO:0000305"
FT CONFLICT 171
FT /note="A -> V (in Ref. 3; AAF18391)"
FT /evidence="ECO:0000305"
FT CONFLICT 206
FT /note="T -> P (in Ref. 7; AAF66736)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 630 AA; 71106 MW; D63021651806620B CRC64;
MQGGNSGVRK REEEGDGAGA VAAPPAIDFP AEGPDPEYDE SDVPAEIQVL KEPLQQPTFP
FAVANQLLLV SLLEHLSHVH EPNPLRSRQV FKLLCQTFIK MGLLSSFTCS DEFSSLRLHH
NRAITHLMRS AKERVRQDPC EDISRIQKIR SREVALEAQT SRYLNEFEEL AILGKGGYGR
VYKVRNKLDG QYYAIKKILI KGATKTVCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVI
QPRADRAAIE LPSLEVLSDQ EEDREQCGVK NDESSSSSII FAEPTPEKEK RFGESDTENQ
NNKSVKYTTN LVIRESGELE STLELQENGL AGLSASSIVE QQLPLRRNSH LEESFTSTEE
SSEENVNFLG QTEAQYHLML HIQMQLCELS LWDWIVERNK RGREYVDESA CPYVMANVAT
KIFQELVEGV FYIHNMGIVH RDLKPRNIFL HGPDQQVKIG DFGLACTDIL QKNTDWTNRN
GKRTPTHTSR VGTCLYASPE QLEGSEYDAK SDMYSLGVVL LELFQPFGTE MERAEVLTGL
RTGQLPESLR KRCPVQAKYI QHLTRRNSSQ RPSAIQLLQS ELFQNSGNVN LTLQMKIIEQ
EKEIAELKKQ LNLLSQDKGV RDDGKDGGVG
