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E2AK1_RAT
ID   E2AK1_RAT               Reviewed;         620 AA.
AC   Q63185; Q642C7;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   05-APR-2011, sequence version 2.
DT   03-AUG-2022, entry version 152.
DE   RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 1 {ECO:0000305};
DE            EC=2.7.11.1 {ECO:0000250|UniProtKB:Q9Z2R9};
DE   AltName: Full=Heme-controlled repressor;
DE            Short=HCR;
DE   AltName: Full=Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase {ECO:0000250|UniProtKB:Q9BQI3};
DE   AltName: Full=Heme-regulated inhibitor {ECO:0000303|PubMed:20071449};
DE   AltName: Full=Hemin-sensitive initiation factor 2-alpha kinase {ECO:0000303|PubMed:7908290};
GN   Name=Eif2ak1 {ECO:0000312|RGD:70883};
GN   Synonyms=Hri {ECO:0000303|PubMed:20071449};
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC   STRAIN=Sprague-Dawley; TISSUE=Brain;
RX   PubMed=7908290; DOI=10.1016/s0021-9258(17)34044-9;
RA   Mellor H., Flowers K.M., Kimball S.R., Jefferson L.S.;
RT   "Cloning and characterization of cDNA encoding rat hemin-sensitive
RT   initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue
RT   expression.";
RL   J. Biol. Chem. 269:10201-10204(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Brown Norway; TISSUE=Testis;
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   [4]
RP   TISSUE SPECIFICITY, AND INDUCTION.
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   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-283, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
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. Key
CC       activator of the integrated stress response (ISR) required for
CC       adaptation to various stress, such as heme deficiency, oxidative
CC       stress, osmotic shock, mitochondrial dysfunction and heat shock.
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. Acts as a key sensor of heme-deficiency: in normal
CC       conditions, binds hemin via a cysteine thiolate and histidine
CC       nitrogenous coordination, leading to inhibit the protein kinase
CC       activity. This binding occurs with moderate affinity, allowing it to
CC       sense the heme concentration within the cell: heme depletion relieves
CC       inhibition and stimulates kinase activity, activating the ISR. Thanks
CC       to this unique heme-sensing capacity, plays a crucial role to shut off
CC       protein synthesis during acute heme-deficient conditions. In red blood
CC       cells (RBCs), controls hemoglobin synthesis ensuring a coordinated
CC       regulation of the synthesis of its heme and globin moieties. It thereby
CC       plays an essential protective role for RBC survival in anemias of iron
CC       deficiency. Similarly, in hepatocytes, involved in heme-mediated
CC       translational control of CYP2B and CYP3A and possibly other hepatic
CC       P450 cytochromes. May also regulate endoplasmic reticulum (ER) stress
CC       during acute heme-deficient conditions (By similarity). Also activates
CC       the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein
CC       kinase activity is activated upon binding to the processed form of
CC       DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (By
CC       similarity). {ECO:0000250|UniProtKB:Q9BQI3,
CC       ECO:0000250|UniProtKB:Q9Z2R9}.
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:0000250|UniProtKB:Q9Z2R9};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC         Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
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. Induced by
CC       oxidative stress generated by arsenite treatment. Binding of nitric
CC       oxide (NO) to the heme iron in the N-terminal heme-binding domain
CC       activates the kinase activity, while binding of carbon monoxide (CO)
CC       suppresses kinase activity (By similarity). Protein kinase activity is
CC       also 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:0000250|UniProtKB:Q9Z2R9}.
CC   -!- SUBUNIT: Synthesized in an inactive form that binds to the N-terminal
CC       domain of CDC37. Has to be associated with a multiprotein complex
CC       containing Hsp90, CDC37 and PPP5C for maturation and activation by
CC       autophosphorylation. The phosphatase PPP5C modulates this activation
CC       (By similarity). Homodimer; homodimerizes in presence of heme, forming
CC       a disulfide-linked inactive homodimer (By similarity). Interacts with
CC       DELE1; binds to the processed form of DELE1 (S-DELE1) in response to
CC       mitochondrial stress, leading to activate its protein kinase activity
CC       and trigger the integrated stress response (ISR) (By similarity).
CC       {ECO:0000250|UniProtKB:P33279, ECO:0000250|UniProtKB:Q9BQI3}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2R9}.
CC   -!- TISSUE SPECIFICITY: Expressed predominantly in erythroid cells. At much
CC       lower levels, expressed in hepatocytes (at protein level).
CC       {ECO:0000269|PubMed:20071449}.
CC   -!- INDUCTION: Induced by various cytochrome P450 inducers, including
CC       phenobarbital, dexamethasone, rifampicin and barbituric acid in its
CC       autophosphorylated state. Carbamazepine has no effect.
CC       {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-486 is required for kinase activation. The
CC       active autophosphorylated form apparently is largely refractory to
CC       cellular heme fluctuations. {ECO:0000250|UniProtKB:Q9Z2R9}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC       kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR   EMBL; L27707; AAA18255.1; -; mRNA.
DR   EMBL; CH474012; EDL89653.1; -; Genomic_DNA.
DR   EMBL; BC081838; AAH81838.1; -; mRNA.
DR   PIR; A53731; A53731.
DR   RefSeq; NP_037355.1; NM_013223.1.
DR   AlphaFoldDB; Q63185; -.
DR   STRING; 10116.ENSRNOP00000001392; -.
DR   iPTMnet; Q63185; -.
DR   PhosphoSitePlus; Q63185; -.
DR   PaxDb; Q63185; -.
DR   Ensembl; ENSRNOT00000001392; ENSRNOP00000001392; ENSRNOG00000001050.
DR   GeneID; 27137; -.
DR   KEGG; rno:27137; -.
DR   CTD; 27102; -.
DR   RGD; 70883; Eif2ak1.
DR   eggNOG; KOG1035; Eukaryota.
DR   GeneTree; ENSGT00940000157605; -.
DR   InParanoid; Q63185; -.
DR   OrthoDB; 64059at2759; -.
DR   PhylomeDB; Q63185; -.
DR   TreeFam; TF329383; -.
DR   PRO; PR:Q63185; -.
DR   Proteomes; UP000002494; Chromosome 12.
DR   Proteomes; UP000234681; Chromosome 12.
DR   Bgee; ENSRNOG00000001050; Expressed in spleen and 20 other tissues.
DR   ExpressionAtlas; Q63185; baseline and differential.
DR   Genevisible; Q63185; RN.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:RGD.
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; ISO:RGD.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0002526; P:acute inflammatory response; ISO:RGD.
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; ISO:RGD.
DR   GO; GO:0030225; P:macrophage differentiation; ISO:RGD.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0046986; P:negative regulation of hemoglobin biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0017148; P:negative regulation of translation; IEA:UniProtKB-KW.
DR   GO; GO:0006909; P:phagocytosis; ISO:RGD.
DR   GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR   GO; GO:0046501; P:protoporphyrinogen IX metabolic process; ISO:RGD.
DR   GO; GO:0010999; P:regulation of eIF2 alpha phosphorylation by heme; ISO:RGD.
DR   GO; GO:0046984; P:regulation of hemoglobin biosynthetic process; ISO:RGD.
DR   GO; GO:0006417; P:regulation of translation; ISO:RGD.
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..620
FT                   /note="Eukaryotic translation initiation factor 2-alpha
FT                   kinase 1"
FT                   /id="PRO_0000085944"
FT   DOMAIN          167..581
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REPEAT          408..413
FT                   /note="HRM 1"
FT   REPEAT          550..555
FT                   /note="HRM 2"
FT   REGION          1..38
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:0007744|PubMed:22673903"
FT   MOD_RES         484
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   MOD_RES         486
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   MOD_RES         491
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   CONFLICT        398
FT                   /note="N -> K (in Ref. 1; AAA18255)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        402
FT                   /note="E -> K (in Ref. 1; AAA18255)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   620 AA;  69586 MW;  A4E56A2FBFCCEDDC CRC64;
     MLGGGSVDGE RDTDDDAAGA VAAPPAIDFP AEVSDPKYDE SDVPAELQVF KEPLQQPTFP
     FLVANQLLLV SLLEHLSHVH EPNPLHSKQV FKLLCQTFIK MGLLSSFTCS DEFSSLRLHH
     NRAITHLMRS AKERVRQDPC QDNSYMQKIR SREIALEAQT SRYLNEFEEL AILGKGGYGR
     VYKVRNKLDG QHYAIKKILI KSATKTDCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVL
     QPQDRVPIQL PSLEVLSEHE GDRNQGGVKD NESSSSIIFA ELTPEKENPL AESDVKNENN
     NLVSYRANLV IRSSSESESS IELQEDGLNE SPLRPVVKHQ LPLGHSSDVE GNFTSTDESS
     EDNLNLLGQT EARYHLMLHI QMQLCELSLW DWIAERNNRS RECVDEAACP YVMASVATKI
     FQELVEGVFY IHNMGIVHRD LKPRNIFLHG PDQQVKIGDF GLACADIIQK SADWTNRNGK
     GTPTHTSRVG TCLYASPEQL EGSEYDAKSD MYSLGVILLE LFQPFGTEME RATVLTGVRT
     GRIPESLSKR CPVQAKYIQL LTGRNAAQRP SALQLLQSEL FQTTGNVNLT LQMKIMEQEK
     EIEELKKQLS LLSQDKGLKR
 
 
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