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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
 
 
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