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Protein

Eukaryotic translation initiation factor 2-alpha kinase 1

Gene

Eif2ak1

Organism
Rattus norvegicus (Rat)
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 (By similarity). 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 sitei440 – 4401Proton 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

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
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 12

Organism-specific databases

RGDi70883. Eif2ak1.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 620620Eukaryotic translation initiation factor 2-alpha kinase 1PRO_0000085944Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei283 – 2831PhosphothreonineCombined sources
Modified residuei484 – 4841Phosphothreonine; by autocatalysisBy similarity
Modified residuei486 – 4861Phosphothreonine; by autocatalysisBy similarity
Modified residuei491 – 4911PhosphothreonineBy similarity

Post-translational modificationi

Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-486 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

PaxDbiQ63185.
PRIDEiQ63185.

PTM databases

iPTMnetiQ63185.
PhosphoSiteiQ63185.

Expressioni

Tissue specificityi

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

Inductioni

Induced by various cytochrome P450 inducers, including phenobarbital, dexamethasone, rifampicin and barbituric acid in its autophosphorylated state. Carbamazepine has no effect.1 Publication

Gene expression databases

BgeeiENSRNOG00000001050.
ExpressionAtlasiQ63185. baseline and differential.
GenevisibleiQ63185. RN.

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 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

STRINGi10116.ENSRNOP00000001392.

Structurei

3D structure databases

ProteinModelPortaliQ63185.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini167 – 581415Protein kinasePROSITE-ProRule annotationAdd
BLAST
Repeati408 – 4136HRM 1
Repeati550 – 5556HRM 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.
HOGENOMiHOG000006880.
HOVERGENiHBG051429.
InParanoidiQ63185.
KOiK16194.
PhylomeDBiQ63185.
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.

Q63185-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLGGGSVDGE RDTDDDAAGA VAAPPAIDFP AEVSDPKYDE SDVPAELQVF
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
SREIALEAQT SRYLNEFEEL AILGKGGYGR VYKVRNKLDG QHYAIKKILI
210 220 230 240 250
KSATKTDCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVL QPQDRVPIQL
260 270 280 290 300
PSLEVLSEHE GDRNQGGVKD NESSSSIIFA ELTPEKENPL AESDVKNENN
310 320 330 340 350
NLVSYRANLV IRSSSESESS IELQEDGLNE SPLRPVVKHQ LPLGHSSDVE
360 370 380 390 400
GNFTSTDESS EDNLNLLGQT EARYHLMLHI QMQLCELSLW DWIAERNNRS
410 420 430 440 450
RECVDEAACP YVMASVATKI FQELVEGVFY IHNMGIVHRD LKPRNIFLHG
460 470 480 490 500
PDQQVKIGDF GLACADIIQK SADWTNRNGK GTPTHTSRVG TCLYASPEQL
510 520 530 540 550
EGSEYDAKSD MYSLGVILLE LFQPFGTEME RATVLTGVRT GRIPESLSKR
560 570 580 590 600
CPVQAKYIQL LTGRNAAQRP SALQLLQSEL FQTTGNVNLT LQMKIMEQEK
610 620
EIEELKKQLS LLSQDKGLKR
Length:620
Mass (Da):69,586
Last modified:April 5, 2011 - v2
Checksum:iA4E56A2FBFCCEDDC
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti398 – 3981N → K in AAA18255 (PubMed:7908290).Curated
Sequence conflicti402 – 4021E → K in AAA18255 (PubMed:7908290).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L27707 mRNA. Translation: AAA18255.1.
CH474012 Genomic DNA. Translation: EDL89653.1.
BC081838 mRNA. Translation: AAH81838.1.
PIRiA53731.
RefSeqiNP_037355.1. NM_013223.1.
UniGeneiRn.3333.

Genome annotation databases

EnsembliENSRNOT00000001392; ENSRNOP00000001392; ENSRNOG00000001050.
GeneIDi27137.
KEGGirno:27137.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L27707 mRNA. Translation: AAA18255.1.
CH474012 Genomic DNA. Translation: EDL89653.1.
BC081838 mRNA. Translation: AAH81838.1.
PIRiA53731.
RefSeqiNP_037355.1. NM_013223.1.
UniGeneiRn.3333.

3D structure databases

ProteinModelPortaliQ63185.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000001392.

PTM databases

iPTMnetiQ63185.
PhosphoSiteiQ63185.

Proteomic databases

PaxDbiQ63185.
PRIDEiQ63185.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000001392; ENSRNOP00000001392; ENSRNOG00000001050.
GeneIDi27137.
KEGGirno:27137.

Organism-specific databases

CTDi27102.
RGDi70883. Eif2ak1.

Phylogenomic databases

eggNOGiENOG410ISBT. Eukaryota.
ENOG410YD23. LUCA.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000006880.
HOVERGENiHBG051429.
InParanoidiQ63185.
KOiK16194.
PhylomeDBiQ63185.
TreeFamiTF329383.

Miscellaneous databases

PROiQ63185.

Gene expression databases

BgeeiENSRNOG00000001050.
ExpressionAtlasiQ63185. baseline and differential.
GenevisibleiQ63185. RN.

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_RAT
AccessioniPrimary (citable) accession number: Q63185
Secondary accession number(s): Q642C7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: April 5, 2011
Last modified: September 7, 2016
This is version 126 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 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.