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Protein

Eukaryotic translation initiation factor 2-alpha kinase 1

Gene

EIF2AK1

Organism
Homo sapiens (Human)
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 (By similarity).By similarity

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 (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei80 – 801Heme-bindingBy similarity
Binding sitei196 – 1961ATPPROSITE-ProRule annotation
Active sitei442 – 4421Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi173 – 1819ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

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

Keywords - Ligandi

ATP-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

HGNCiHGNC:24921. EIF2AK1.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA134919097.

Chemistry

ChEMBLiCHEMBL6029.
GuidetoPHARMACOLOGYi2015.

Polymorphism and mutation databases

BioMutaiEIF2AK1.
DMDMi32172458.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 630630Eukaryotic translation initiation factor 2-alpha kinase 1PRO_0000085941Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei285 – 2851PhosphothreonineBy similarity
Modified residuei486 – 4861Phosphothreonine; by autocatalysisBy similarity
Modified residuei488 – 4881Phosphothreonine; by autocatalysisBy similarity
Modified residuei493 – 4931PhosphothreonineBy similarity

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.

PTM databases

iPTMnetiQ9BQI3.
PhosphoSiteiQ9BQI3.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000086232.
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. 7 interactions.
IntActiQ9BQI3. 4 interactions.
MINTiMINT-4715350.
STRINGi9606.ENSP00000199389.

Chemistry

BindingDBiQ9BQI3.

Structurei

3D structure databases

ProteinModelPortaliQ9BQI3.
SMRiQ9BQI3. Positions 176-227, 316-614.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini167 – 583417Protein kinasePROSITE-ProRule annotationAdd
BLAST
Repeati410 – 4156HRM 1
Repeati552 – 5576HRM 2

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.
InParanoidiQ9BQI3.
KOiK16194.
OMAiEGVCYIH.
OrthoDBiEOG091G03OR.
PhylomeDBiQ9BQI3.
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]

Sequences (2)i

Sequence statusi: Complete.

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

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

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti2 – 21Q → L in AAF18391 (Ref. 3) Curated
Sequence conflicti4 – 41G → D in BAF83016 (PubMed:14702039).Curated
Sequence conflicti24 – 329PPAIDFPAE → RRHRLSRR in AAF70289 (PubMed:11101152).Curated
Sequence conflicti137 – 1371Q → R in AAF70289 (PubMed:11101152).Curated
Sequence conflicti149 – 1491I → T in BAF83016 (PubMed:14702039).Curated
Sequence conflicti171 – 1711A → V in AAF18391 (Ref. 3) Curated
Sequence conflicti206 – 2061T → P in AAF66736 (PubMed:12391722).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti117 – 1171R → T.1 Publication
Corresponds to variant rs34889754 [ dbSNP | Ensembl ].
VAR_040466
Natural varianti132 – 1321K → T.1 Publication
Corresponds to variant rs34851195 [ dbSNP | Ensembl ].
VAR_040467
Natural varianti134 – 1341R → K.1 Publication
Corresponds to variant rs55744865 [ dbSNP | Ensembl ].
VAR_040468
Natural varianti139 – 1391P → S.1 Publication
Corresponds to variant rs55963745 [ dbSNP | Ensembl ].
VAR_040469
Natural varianti145 – 1451R → H.1 Publication
Corresponds to variant rs55971369 [ dbSNP | Ensembl ].
VAR_040470
Natural varianti202 – 2021G → S in a lung adenocarcinoma sample; somatic mutation. 1 Publication
VAR_040471
Natural varianti292 – 2921F → L.1 Publication
Corresponds to variant rs55982710 [ dbSNP | Ensembl ].
VAR_040472
Natural varianti319 – 3191L → H.1 Publication
Corresponds to variant rs34909691 [ dbSNP | Ensembl ].
VAR_040473
Natural varianti558 – 5581K → R.3 Publications
Corresponds to variant rs2640 [ dbSNP | Ensembl ].
VAR_015732

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei244 – 2441Missing in isoform 2. 3 PublicationsVSP_007589

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

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.
SMRiQ9BQI3. Positions 176-227, 316-614.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118002. 7 interactions.
IntActiQ9BQI3. 4 interactions.
MINTiMINT-4715350.
STRINGi9606.ENSP00000199389.

Chemistry

BindingDBiQ9BQI3.
ChEMBLiCHEMBL6029.
GuidetoPHARMACOLOGYi2015.

PTM databases

iPTMnetiQ9BQI3.
PhosphoSiteiQ9BQI3.

Polymorphism and mutation databases

BioMutaiEIF2AK1.
DMDMi32172458.

Proteomic databases

EPDiQ9BQI3.
MaxQBiQ9BQI3.
PaxDbiQ9BQI3.
PeptideAtlasiQ9BQI3.
PRIDEiQ9BQI3.

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.
GeneCardsiEIF2AK1.
H-InvDBHIX0003741.
HGNCiHGNC:24921. EIF2AK1.
HPAiCAB022082.
HPA016496.
HPA061675.
neXtProtiNX_Q9BQI3.
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.
PROiQ9BQI3.

Gene expression databases

BgeeiENSG00000086232.
CleanExiHS_EIF2AK1.
ExpressionAtlasiQ9BQI3. baseline and differential.
GenevisibleiQ9BQI3. HS.

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_HUMAN
AccessioniPrimary (citable) accession number: Q9BQI3
Secondary accession number(s): A8K2R2
, Q549K6, Q8NBW3, Q9HC02, Q9NYE0, Q9P0V6, Q9P1J5, Q9P2H8, Q9UHG4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 11, 2001
Last sequence update: June 20, 2003
Last modified: September 7, 2016
This is version 162 of the entry and version 2 of the sequence. [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

Miscellaneous

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 7
    Human chromosome 7: entries, gene names and cross-references to MIM
  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 and mouse protein kinases
    Human and mouse protein kinases: classification and index
  5. 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.