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Protein

Eukaryotic translation initiation factor 2-alpha kinase 1

Gene

EIF2AK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (By similarity).By similarity

Miscellaneous

Can bind 1 molecules of heme per polypeptide chain.By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Activity 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 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei80Heme-bindingBy similarity1
Binding sitei196ATPPROSITE-ProRule annotation1
Active sitei442Proton 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: GO_Central

GO - Biological processi

Keywordsi

Molecular functionKinase, Protein synthesis inhibitor, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

SignaLinkiQ9BQI3
SIGNORiQ9BQI3

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, KIAA1369
ORF Names:PRO1362
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 7

Organism-specific databases

EuPathDBiHostDB:ENSG00000086232.12
HGNCiHGNC:24921 EIF2AK1
neXtProtiNX_Q9BQI3

Subcellular locationi

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Organism-specific databases

DisGeNETi27102
OpenTargetsiENSG00000086232
PharmGKBiPA134919097

Chemistry databases

ChEMBLiCHEMBL6029
GuidetoPHARMACOLOGYi2015

Polymorphism and mutation databases

BioMutaiEIF2AK1
DMDMi32172458

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000859411 – 630Eukaryotic translation initiation factor 2-alpha kinase 1Add BLAST630

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei285PhosphothreonineBy similarity1
Modified residuei486Phosphothreonine; by autocatalysisBy similarity1
Modified residuei488Phosphothreonine; by autocatalysisBy similarity1
Modified residuei493PhosphothreonineBy similarity1

Post-translational modificationi

Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-488 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Phosphoprotein

Proteomic databases

EPDiQ9BQI3
MaxQBiQ9BQI3
PaxDbiQ9BQI3
PeptideAtlasiQ9BQI3
PRIDEiQ9BQI3
ProteomicsDBi78682
78683 [Q9BQI3-2]

PTM databases

iPTMnetiQ9BQI3
PhosphoSitePlusiQ9BQI3

Expressioni

Tissue specificityi

Expressed predominantly in erythroid cells. At much lower levels, expressed in hepatocytes (at protein level).1 Publication

Gene expression databases

BgeeiENSG00000086232 Expressed in 226 organ(s), highest expression level in trabecular bone tissue
CleanExiHS_EIF2AK1
ExpressionAtlasiQ9BQI3 baseline and differential
GenevisibleiQ9BQI3 HS

Organism-specific databases

HPAiCAB022082
HPA016496
HPA061675

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. Forms oligomers. Has been reported as a non-covalently bound 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).By similarity

GO - Molecular functioni

Protein-protein interaction databases

BioGridi118002, 15 interactors
IntActiQ9BQI3, 5 interactors
STRINGi9606.ENSP00000199389

Chemistry databases

BindingDBiQ9BQI3

Structurei

3D structure databases

ProteinModelPortaliQ9BQI3
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini167 – 583Protein kinasePROSITE-ProRule annotationAdd BLAST417
Repeati410 – 415HRM 16
Repeati552 – 557HRM 26

Sequence similaritiesi

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

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410ISBT Eukaryota
ENOG410YD23 LUCA
GeneTreeiENSGT00530000062984
HOVERGENiHBG051429
InParanoidiQ9BQI3
KOiK16194
OMAiEGVCYIH
OrthoDBiEOG091G03OR
PhylomeDBiQ9BQI3
TreeFamiTF329383

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q9BQI3-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MQGGNSGVRK REEEGDGAGA VAAPPAIDFP AEGPDPEYDE SDVPAEIQVL
60 70 80 90 100
KEPLQQPTFP FAVANQLLLV SLLEHLSHVH EPNPLRSRQV FKLLCQTFIK
110 120 130 140 150
MGLLSSFTCS DEFSSLRLHH NRAITHLMRS AKERVRQDPC EDISRIQKIR
160 170 180 190 200
SREVALEAQT SRYLNEFEEL AILGKGGYGR VYKVRNKLDG QYYAIKKILI
210 220 230 240 250
KGATKTVCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVI QPRADRAAIE
260 270 280 290 300
LPSLEVLSDQ EEDREQCGVK NDESSSSSII FAEPTPEKEK RFGESDTENQ
310 320 330 340 350
NNKSVKYTTN LVIRESGELE STLELQENGL AGLSASSIVE QQLPLRRNSH
360 370 380 390 400
LEESFTSTEE SSEENVNFLG QTEAQYHLML HIQMQLCELS LWDWIVERNK
410 420 430 440 450
RGREYVDESA CPYVMANVAT KIFQELVEGV FYIHNMGIVH RDLKPRNIFL
460 470 480 490 500
HGPDQQVKIG DFGLACTDIL QKNTDWTNRN GKRTPTHTSR VGTCLYASPE
510 520 530 540 550
QLEGSEYDAK SDMYSLGVVL LELFQPFGTE MERAEVLTGL RTGQLPESLR
560 570 580 590 600
KRCPVQAKYI QHLTRRNSSQ RPSAIQLLQS ELFQNSGNVN LTLQMKIIEQ
610 620 630
EKEIAELKKQ LNLLSQDKGV RDDGKDGGVG
Length:630
Mass (Da):71,106
Last modified:June 20, 2003 - v2
Checksum:iD63021651806620B
GO
Isoform 2 (identifier: Q9BQI3-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     244-244: Missing.

Show »
Length:629
Mass (Da):71,035
Checksum:iB90159795D580809
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H7C033H7C033_HUMAN
Eukaryotic translation initiation f...
EIF2AK1
72Annotation score:
C9J7U7C9J7U7_HUMAN
Eukaryotic translation initiation f...
EIF2AK1
164Annotation score:
F8WCM0F8WCM0_HUMAN
Eukaryotic translation initiation f...
EIF2AK1
81Annotation score:

Sequence cautioni

The sequence AAF70289 differs from that shown. Reason: Frameshift at positions 24, 26 and 33.Curated
The sequence AAF71057 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA92607 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti2Q → L in AAF18391 (Ref. 3) Curated1
Sequence conflicti4G → D in BAF83016 (PubMed:14702039).Curated1
Sequence conflicti24 – 32PPAIDFPAE → RRHRLSRR in AAF70289 (PubMed:11101152).Curated9
Sequence conflicti137Q → R in AAF70289 (PubMed:11101152).Curated1
Sequence conflicti149I → T in BAF83016 (PubMed:14702039).Curated1
Sequence conflicti171A → V in AAF18391 (Ref. 3) Curated1
Sequence conflicti206T → P in AAF66736 (PubMed:12391722).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040466117R → T1 PublicationCorresponds to variant dbSNP:rs34889754Ensembl.1
Natural variantiVAR_040467132K → T1 PublicationCorresponds to variant dbSNP:rs34851195Ensembl.1
Natural variantiVAR_040468134R → K1 PublicationCorresponds to variant dbSNP:rs55744865Ensembl.1
Natural variantiVAR_040469139P → S1 PublicationCorresponds to variant dbSNP:rs55963745Ensembl.1
Natural variantiVAR_040470145R → H1 PublicationCorresponds to variant dbSNP:rs55971369Ensembl.1
Natural variantiVAR_040471202G → S in a lung adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040472292F → L1 PublicationCorresponds to variant dbSNP:rs55982710Ensembl.1
Natural variantiVAR_040473319L → H1 PublicationCorresponds to variant dbSNP:rs34909691Ensembl.1
Natural variantiVAR_015732558K → R3 PublicationsCorresponds to variant dbSNP:rs2640Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_007589244Missing in isoform 2. 3 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF255050 mRNA Translation: AAF70289.1 Frameshift.
AF100784 mRNA Translation: AAP97223.1
AF181071 mRNA Translation: AAF18391.1
AB037790 mRNA Translation: BAA92607.1 Different initiation.
AF183414 mRNA Translation: AAG09683.1
AL136563 mRNA Translation: CAB66498.1
AF147094 mRNA Translation: AAF66736.1
AK075192 mRNA Translation: BAC11461.1
AK290327 mRNA Translation: BAF83016.1
AL834494 mRNA Translation: CAD39152.1
CH236963 Genomic DNA Translation: EAL23714.1
CH878731 Genomic DNA Translation: EAW55049.1
BC006524 mRNA Translation: AAH06524.1
AF116634 mRNA Translation: AAF71057.1 Different initiation.
CCDSiCCDS5345.1 [Q9BQI3-1]
RefSeqiNP_001127807.1, NM_001134335.1 [Q9BQI3-2]
NP_055228.2, NM_014413.3 [Q9BQI3-1]
UniGeneiHs.520205

Genome annotation databases

EnsembliENST00000199389; ENSP00000199389; ENSG00000086232 [Q9BQI3-1]
GeneIDi27102
KEGGihsa:27102
UCSCiuc003spp.4 human [Q9BQI3-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF255050 mRNA Translation: AAF70289.1 Frameshift.
AF100784 mRNA Translation: AAP97223.1
AF181071 mRNA Translation: AAF18391.1
AB037790 mRNA Translation: BAA92607.1 Different initiation.
AF183414 mRNA Translation: AAG09683.1
AL136563 mRNA Translation: CAB66498.1
AF147094 mRNA Translation: AAF66736.1
AK075192 mRNA Translation: BAC11461.1
AK290327 mRNA Translation: BAF83016.1
AL834494 mRNA Translation: CAD39152.1
CH236963 Genomic DNA Translation: EAL23714.1
CH878731 Genomic DNA Translation: EAW55049.1
BC006524 mRNA Translation: AAH06524.1
AF116634 mRNA Translation: AAF71057.1 Different initiation.
CCDSiCCDS5345.1 [Q9BQI3-1]
RefSeqiNP_001127807.1, NM_001134335.1 [Q9BQI3-2]
NP_055228.2, NM_014413.3 [Q9BQI3-1]
UniGeneiHs.520205

3D structure databases

ProteinModelPortaliQ9BQI3
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118002, 15 interactors
IntActiQ9BQI3, 5 interactors
STRINGi9606.ENSP00000199389

Chemistry databases

BindingDBiQ9BQI3
ChEMBLiCHEMBL6029
GuidetoPHARMACOLOGYi2015

PTM databases

iPTMnetiQ9BQI3
PhosphoSitePlusiQ9BQI3

Polymorphism and mutation databases

BioMutaiEIF2AK1
DMDMi32172458

Proteomic databases

EPDiQ9BQI3
MaxQBiQ9BQI3
PaxDbiQ9BQI3
PeptideAtlasiQ9BQI3
PRIDEiQ9BQI3
ProteomicsDBi78682
78683 [Q9BQI3-2]

Protocols and materials databases

DNASUi27102
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000199389; ENSP00000199389; ENSG00000086232 [Q9BQI3-1]
GeneIDi27102
KEGGihsa:27102
UCSCiuc003spp.4 human [Q9BQI3-1]

Organism-specific databases

CTDi27102
DisGeNETi27102
EuPathDBiHostDB:ENSG00000086232.12
GeneCardsiEIF2AK1
H-InvDBiHIX0003741
HGNCiHGNC:24921 EIF2AK1
HPAiCAB022082
HPA016496
HPA061675
neXtProtiNX_Q9BQI3
OpenTargetsiENSG00000086232
PharmGKBiPA134919097
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ISBT Eukaryota
ENOG410YD23 LUCA
GeneTreeiENSGT00530000062984
HOVERGENiHBG051429
InParanoidiQ9BQI3
KOiK16194
OMAiEGVCYIH
OrthoDBiEOG091G03OR
PhylomeDBiQ9BQI3
TreeFamiTF329383

Enzyme and pathway databases

SignaLinkiQ9BQI3
SIGNORiQ9BQI3

Miscellaneous databases

ChiTaRSiEIF2AK1 human
GeneWikiiEIF2AK1
GenomeRNAii27102
PROiPR:Q9BQI3

Gene expression databases

BgeeiENSG00000086232 Expressed in 226 organ(s), highest expression level in trabecular bone tissue
CleanExiHS_EIF2AK1
ExpressionAtlasiQ9BQI3 baseline and differential
GenevisibleiQ9BQI3 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiE2AK1_HUMAN
AccessioniPrimary (citable) accession number: Q9BQI3
Secondary accession number(s): A8K2R2
, Q549K6, Q8NBW3, Q9HC02, Q9NYE0, Q9P0V6, Q9P1J5, Q9P2H8, Q9UHG4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 11, 2001
Last sequence update: June 20, 2003
Last modified: November 7, 2018
This is version 178 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. Human chromosome 7
    Human chromosome 7: entries, gene names and cross-references to MIM
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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