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Protein

Eukaryotic translation initiation factor 2-alpha kinase 1

Gene

Eif2ak1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser-48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Induced by acute heme depletion, that not only increases EIF2AK1 protein levels, but also stimulates kinase activity by autophosphorylation. Inhibited by the heme-degradation products biliverdin and bilirubin. Induced by oxidative stress generated by arsenite treatment. Binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei80Heme-bindingBy similarity1
Binding sitei196ATPPROSITE-ProRule annotation1
Active sitei440Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi173 – 181ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • eukaryotic translation initiation factor 2alpha kinase activity Source: UniProtKB
  • heme binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase activity Source: MGI

GO - Biological processi

  • acute inflammatory response Source: MGI
  • iron ion homeostasis Source: MGI
  • macrophage differentiation Source: MGI
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of hemoglobin biosynthetic process Source: UniProtKB
  • negative regulation of translation Source: UniProtKB-KW
  • phagocytosis Source: MGI
  • protein autophosphorylation Source: UniProtKB
  • protoporphyrinogen IX metabolic process Source: MGI
  • regulation of eIF2 alpha phosphorylation by heme Source: MGI
  • regulation of hemoglobin biosynthetic process Source: MGI
  • regulation of translation Source: MGI
  • response to external stimulus Source: UniProtKB
  • response to stress Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Protein synthesis inhibitor, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Eukaryotic translation initiation factor 2-alpha kinase 1 (EC:2.7.11.1)
Alternative name(s):
Heme-controlled repressor
Short name:
HCR
Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase
Heme-regulated inhibitor
Hemin-sensitive initiation factor 2-alpha kinase
Gene namesi
Name:Eif2ak1
Synonyms:Hri
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:1353448. Eif2ak1.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Involvement in diseasei

Defects in Eif2ak1 are a cause of hyperchromic anemia in animals suffering from iron deficiency. The number of red blood cells is decreased due to increased apoptosis of erythroid precursor cells, probably because globins misfold and aggregate in the absence of heme.

Disruption phenotypei

Mice are viable and fertile without gross morphological abnormalities. Dramatically altered response to diet-induced iron deficiency shifting from an adaptive decrease in RBC volume and intracellular hemoglobin content to an increased production of abnormally dense red blood cells (RBCs) with decreasing red cell counts. The decrease in RBC number is the result of increased apoptosis of erythroid precursors. Diminished levels of phosphorylated EIF2S1 in bone marrow-derived macrophages (BMDMs). Impaired maturation of BMDMs and blunted inflammatory response to LPS with a reduced cytokine production. Impaired phagocytosis of senescent RBCs by macrophages, resulting in a lower phagocytosis index and lower percentage of macrophages with ingested RBC. In hepatocytes, cytochromes P450 CYP2B6 and CYP3A induction by phenobarbital is not impaired in response to acute heme depletion and CYP2B6 and CYP3A proteins continue to accumulate to supranormal levels, irrespective of the hepatic heme pool status. These cells also exhibit a weak, albeit significant, elevation of the basal ER-stress as reflected by elevated levels of autophosphorylated EIF2AK3/PERK and EIF2AK4/GCN2, the ER-stress related chaperones HSPA5 and HSP90B1, and total hepatic protein ubiquitination.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi196K → R: Abolishes kinase activity. 2 Publications1
Mutagenesisi483T → A: No effect on kinase activity. 1 Publication1
Mutagenesisi483T → D: No effect on kinase activity. 1 Publication1
Mutagenesisi485T → A: Abolishes kinase activity. 1 Publication1
Mutagenesisi485T → D: Constitutively active kinase; loss of regulation by heme and arsenite. 1 Publication1
Mutagenesisi490T → A: Almost complete loss of kinase activity; even upon arsenite treatment. 1 Publication1
Mutagenesisi490T → D: Almost complete loss of kinase activity; even upon arsenite treatment. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL1938213.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000859421 – 619Eukaryotic translation initiation factor 2-alpha kinase 1Add BLAST619

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei283PhosphothreonineBy similarity1
Modified residuei483Phosphothreonine; by autocatalysis1 Publication1
Modified residuei485Phosphothreonine; by autocatalysis1 Publication1
Modified residuei490Phosphothreonine; by autocatalysis1 Publication1

Post-translational modificationi

Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-485 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations.1 Publication

Keywords - PTMi

Disulfide bond, Phosphoprotein

Proteomic databases

PaxDbiQ9Z2R9.
PRIDEiQ9Z2R9.

PTM databases

iPTMnetiQ9Z2R9.
PhosphoSitePlusiQ9Z2R9.

Expressioni

Tissue specificityi

Expressed predominantly in erythroid cells, mature reticulocytes, as well as fetal liver nucleated erythroid cells. At much lower levels, expressed in hepatocytes and bone marrow-derived macrophages (at protein level).3 Publications

Developmental stagei

Highly expressed in fetal liver erythroid precursor cells at 14.5 dpc (at protein level).1 Publication

Inductioni

By phenobarbital.1 Publication

Gene expression databases

BgeeiENSMUSG00000029613.
GenevisibleiQ9Z2R9. MM.

Interactioni

Subunit structurei

Synthesized in an inactive form that binds to the N-terminal domain of CDC37. Has to be associated with a multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation and activation by autophosphorylation. The phosphatase PPP5C modulates this activation (By similarity). Forms oligomers. Has been reported as a homodimer, as well as a hexamer in the absence of hemin. Converted to an inactive disulfide linked homodimer in the presence of hemin.By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Eif2s1Q6ZWX66EBI-642878,EBI-1202234

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi200421. 1 interactor.
IntActiQ9Z2R9. 2 interactors.
MINTiMINT-1746990.
STRINGi10090.ENSMUSP00000098056.

Structurei

3D structure databases

ProteinModelPortaliQ9Z2R9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini167 – 580Protein kinasePROSITE-ProRule annotationAdd BLAST414
Repeati408 – 413HRM 16
Repeati549 – 554HRM 26

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410ISBT. Eukaryota.
ENOG410YD23. LUCA.
GeneTreeiENSGT00530000062984.
HOVERGENiHBG051429.
InParanoidiQ9Z2R9.
KOiK16194.
OMAiNADWTNR.
OrthoDBiEOG091G03OR.
PhylomeDBiQ9Z2R9.
TreeFamiTF329383.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9Z2R9-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLGGSSVDGE RDTDDDAAGA VAAPPAIDFP AEVSDPKYDE SDVPAELQVL
60 70 80 90 100
KEPLQQPTFP FLVANQLLLV SLLEHLSHVH EPNPLHSKQV FKLLCQTFIK
110 120 130 140 150
MGLLSSFTCS DEFSSLRLHH NRAITHLMRS AKERVRQDPC QDNSYMQKIR
160 170 180 190 200
SREIAFEAQT SRYLNEFEEL AILGKGGYGR VYKVRNKLDG QHYAIKKILI
210 220 230 240 250
KSATKTDCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVV QPQDRVPIQL
260 270 280 290 300
PSLEVLSEQE GDRDQGGVKD NESSSSIVFA ELTPEKEKPF GESEVKNENN
310 320 330 340 350
NLVSYTANLV VRNSSESESS IELQEDGLTD LSVRPVVRHQ LPLGHSSELE
360 370 380 390 400
GNFTSTDESS EGNLNLLGQT EVRYHLMLHI QMQLCELSLW DWITERNKRS
410 420 430 440 450
REYVDEAACP YVMASVATKI FQELVEGVFY IHNMGIVHRD LKPRNIFLHG
460 470 480 490 500
PDQQVKIGDF GLACADIIQN ADWTNRNGKG TRTHTSRVGT CLYASPEQLE
510 520 530 540 550
GSQYDAKSDM YSLGVILLEL FQPFGTEMER ATVLTGVRTG RIPESLSKRC
560 570 580 590 600
PVQAKYIQLL TGRNVSQRPS ALQLLQSELF QTTGNVNLTL QMKIIEQEKE
610
IEELKKQLSL LSQDRGLKR
Length:619
Mass (Da):69,702
Last modified:April 5, 2011 - v2
Checksum:i39DC5FF950C92F2A
GO

Sequence cautioni

The sequence BAD32438 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti20A → S in BAB32242 (PubMed:16141072).Curated1
Sequence conflicti71S → C in BAB32242 (PubMed:16141072).Curated1
Sequence conflicti138 – 150DPCQD…MQKIR → VSPTGCTLYDKYI in BAB32242 (PubMed:16141072).CuratedAdd BLAST13
Sequence conflicti196 – 197KK → IE in BAB29545 (PubMed:16141072).Curated2
Sequence conflicti371E → D in AAC79201 (PubMed:9822714).Curated1
Sequence conflicti371E → D in AAK55766 (PubMed:11726526).Curated1
Sequence conflicti565V → A in AAH28923 (PubMed:15489334).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF028808 mRNA. Translation: AAC79201.1.
AY033898 mRNA. Translation: AAK55766.1.
AK173160 mRNA. Translation: BAD32438.1. Different initiation.
BC028923 mRNA. Translation: AAH28923.1.
BC111035 mRNA. Translation: AAI11036.1.
AK014775 mRNA. Translation: BAB29545.1.
AK020887 mRNA. Translation: BAB32242.1.
AK032508 mRNA. Translation: BAC27901.1.
RefSeqiNP_038585.2. NM_013557.2.
UniGeneiMm.389709.
Mm.431968.

Genome annotation databases

EnsembliENSMUST00000100487; ENSMUSP00000098056; ENSMUSG00000029613.
GeneIDi15467.
KEGGimmu:15467.
UCSCiuc029vqe.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF028808 mRNA. Translation: AAC79201.1.
AY033898 mRNA. Translation: AAK55766.1.
AK173160 mRNA. Translation: BAD32438.1. Different initiation.
BC028923 mRNA. Translation: AAH28923.1.
BC111035 mRNA. Translation: AAI11036.1.
AK014775 mRNA. Translation: BAB29545.1.
AK020887 mRNA. Translation: BAB32242.1.
AK032508 mRNA. Translation: BAC27901.1.
RefSeqiNP_038585.2. NM_013557.2.
UniGeneiMm.389709.
Mm.431968.

3D structure databases

ProteinModelPortaliQ9Z2R9.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200421. 1 interactor.
IntActiQ9Z2R9. 2 interactors.
MINTiMINT-1746990.
STRINGi10090.ENSMUSP00000098056.

Chemistry databases

ChEMBLiCHEMBL1938213.

PTM databases

iPTMnetiQ9Z2R9.
PhosphoSitePlusiQ9Z2R9.

Proteomic databases

PaxDbiQ9Z2R9.
PRIDEiQ9Z2R9.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000100487; ENSMUSP00000098056; ENSMUSG00000029613.
GeneIDi15467.
KEGGimmu:15467.
UCSCiuc029vqe.1. mouse.

Organism-specific databases

CTDi27102.
MGIiMGI:1353448. Eif2ak1.

Phylogenomic databases

eggNOGiENOG410ISBT. Eukaryota.
ENOG410YD23. LUCA.
GeneTreeiENSGT00530000062984.
HOVERGENiHBG051429.
InParanoidiQ9Z2R9.
KOiK16194.
OMAiNADWTNR.
OrthoDBiEOG091G03OR.
PhylomeDBiQ9Z2R9.
TreeFamiTF329383.

Miscellaneous databases

ChiTaRSiEif2ak1. mouse.
PROiQ9Z2R9.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000029613.
GenevisibleiQ9Z2R9. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiE2AK1_MOUSE
AccessioniPrimary (citable) accession number: Q9Z2R9
Secondary accession number(s): Q2TA96
, Q69ZK8, Q8C024, Q8K123, Q9CTP5, Q9D601
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: April 5, 2011
Last modified: November 2, 2016
This is version 146 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.