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Protein

Interferon-induced, double-stranded RNA-activated protein kinase

Gene

Eif2ak2

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

Functioni

IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including west nile virus (WNV), sindbis virus (SV), foot-and-mouth virus (FMDV), semliki Forest virus (SFV) and lymphocytic choriomeningitis virus (LCMV). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3 and IRS1. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. Regulates proliferation, differentiation and survival of hematopoietic stem/progenitor cells, induction of cytokines and chemokines and plays a role in cortex-dependent memory consolidation.14 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, proinflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei271ATPPROSITE-ProRule annotation1
Active sitei376Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi248 – 256ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • activation of MAPKK activity Source: UniProtKB
  • cellular response to amino acid starvation Source: MGI
  • defense response to virus Source: UniProtKB-KW
  • endoplasmic reticulum unfolded protein response Source: MGI
  • innate immune response Source: UniProtKB-KW
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of osteoblast proliferation Source: UniProtKB
  • negative regulation of translation Source: UniProtKB
  • negative regulation of viral genome replication Source: UniProtKB
  • positive regulation of chemokine production Source: UniProtKB
  • positive regulation of cytokine production Source: UniProtKB
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of NIK/NF-kappaB signaling Source: UniProtKB
  • positive regulation of stress-activated MAPK cascade Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • protein phosphorylation Source: MGI
  • regulation of hematopoietic progenitor cell differentiation Source: UniProtKB
  • regulation of hematopoietic stem cell differentiation Source: UniProtKB
  • regulation of hematopoietic stem cell proliferation Source: UniProtKB
  • regulation of NLRP3 inflammasome complex assembly Source: UniProtKB
  • response to interferon-alpha Source: UniProtKB
  • response to toxic substance Source: InterPro
  • response to virus Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
  • translation Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Antiviral defense, Immunity, Innate immunity, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding, RNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Interferon-induced, double-stranded RNA-activated protein kinase (EC:2.7.11.1)
Alternative name(s):
Eukaryotic translation initiation factor 2-alpha kinase 2
Short name:
eIF-2A protein kinase 2
Interferon-inducible RNA-dependent protein kinase
P1/eIF-2A protein kinase
Protein kinase RNA-activated
Short name:
PKR
Short name:
Protein kinase R1 Publication
Serine/threonine-protein kinase TIK
Tyrosine-protein kinase EIF2AK2 (EC:2.7.10.2)
p68 kinase
Gene namesi
Name:Eif2ak2
Synonyms:Pkr, Prkr, Tik
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:1353449. Eif2ak2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice have significantly elevated numbers of bone marrow derived hematopoietic stem/progenitor cells (HSPCs) and which are more actively proliferating and resistant to stress.1 Publication

Chemistry databases

ChEMBLiCHEMBL1795121.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000859462 – 515Interferon-induced, double-stranded RNA-activated protein kinaseAdd BLAST514

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Cross-linki68Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
Modified residuei96Phosphotyrosine; by autocatalysisBy similarity1
Cross-linki154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
Modified residuei157Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei268Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei409Phosphothreonine; by autocatalysisBy similarity1
Modified residuei414Phosphothreonine; by autocatalysisBy similarity1
Modified residuei419PhosphoserineBy similarity1

Post-translational modificationi

Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-414 is dependent on Thr-409 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation (By similarity).By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ03963.
MaxQBiQ03963.
PaxDbiQ03963.
PeptideAtlasiQ03963.
PRIDEiQ03963.

PTM databases

iPTMnetiQ03963.
PhosphoSitePlusiQ03963.

Expressioni

Tissue specificityi

Expressed in heart, lung, brain, kidney, testes, thymus and bone marrow.

Inductioni

By type I interferons.By similarity

Gene expression databases

BgeeiENSMUSG00000024079.
GenevisibleiQ03963. MM.

Interactioni

Subunit structurei

Homodimer. Interacts with DNAJC3 and STRBP (By similarity). Forms a complex with FANCA, FANCC, FANCG and HSP70 (By similarity). Interacts with ADAR/ADAR1. The inactive form interacts with NCK1. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, TARBP2, NLRP1, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain) (By similarity). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase. The inactive form interacts with GSN. Interacts with IKBKB/IKKB, NPM1, NLRP3 and IRS1.By similarity7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Irs1P355692EBI-2603444,EBI-400825

Protein-protein interaction databases

DIPiDIP-41411N.
IntActiQ03963. 2 interactors.
MINTiMINT-270896.
STRINGi10090.ENSMUSP00000024884.

Structurei

Secondary structure

1515
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi8 – 20Combined sources13
Beta strandi24 – 33Combined sources10
Beta strandi35 – 37Combined sources3
Beta strandi39 – 48Combined sources10
Beta strandi54 – 58Combined sources5
Helixi59 – 74Combined sources16
Helixi96 – 106Combined sources11
Beta strandi111 – 115Combined sources5
Beta strandi119 – 123Combined sources5
Beta strandi126 – 134Combined sources9
Beta strandi136 – 144Combined sources9
Helixi145 – 162Combined sources18

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1X48NMR-A96-170[»]
1X49NMR-A1-84[»]
ProteinModelPortaliQ03963.
SMRiQ03963.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ03963.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini8 – 76DRBM 1PROSITE-ProRule annotationAdd BLAST69
Domaini95 – 162DRBM 2PROSITE-ProRule annotationAdd BLAST68
Domaini242 – 504Protein kinasePROSITE-ProRule annotationAdd BLAST263

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni241 – 515Interaction with TRAF5By similarityAdd BLAST275

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi183 – 187Poly-Ser5
Compositional biasi241 – 247Asp/Glu-rich (acidic)7

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.PROSITE-ProRule annotation
Contains 2 DRBM (double-stranded RNA-binding) domains.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG1033. Eukaryota.
ENOG410XS0B. LUCA.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000234351.
HOVERGENiHBG051430.
InParanoidiQ03963.
KOiK16195.
OMAiELLYICP.
OrthoDBiEOG091G088F.
PhylomeDBiQ03963.
TreeFamiTF317576.

Family and domain databases

Gene3Di3.30.160.20. 2 hits.
InterProiIPR014720. dsRBD_dom.
IPR011009. Kinase-like_dom.
IPR033366. PKR.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR11042:SF102. PTHR11042:SF102. 1 hit.
PfamiPF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00358. DSRM. 2 hits.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50137. DS_RBD. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q03963-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MASDTPGFYM DKLNKYRQMH GVAITYKELS TSGPPHDRRF TFQVLIDEKE
60 70 80 90 100
FPEAKGRSKQ EARNAAAKLA VDILDNENKV DCHTSASEQG LFVGNYIGLV
110 120 130 140 150
NSFAQKKKLS VNYEQCEPNS ELPQRFICKC KIGQTMYGTG SGVTKQEAKQ
160 170 180 190 200
LAAKEAYQKL LKSPPKTAGT SSSVVTSTFS GFSSSSSMTS NGVSQSAPGS
210 220 230 240 250
FSSENVFTNG LGENKRKSGV KVSPDDVQRN KYTLDARFNS DFEDIEEIGL
260 270 280 290 300
GGFGQVFKAK HRIDGKRYAI KRVKYNTEKA EHEVQALAEL NHVNIVQYHS
310 320 330 340 350
CWEGVDYDPE HSMSDTSRYK TRCLFIQMEF CDKGTLEQWM RNRNQSKVDK
360 370 380 390 400
ALILDLYEQI VTGVEYIHSK GLIHRDLKPG NIFLVDERHI KIGDFGLATA
410 420 430 440 450
LENDGKSRTR RTGTLQYMSP EQLFLKHYGK EVDIFALGLI LAELLHTCFT
460 470 480 490 500
ESEKIKFFES LRKGDFSNDI FDNKEKSLLK KLLSEKPKDR PETSEILKTL
510
AEWRNISEKK KRNTC
Length:515
Mass (Da):58,280
Last modified:November 1, 1997 - v2
Checksum:i7A116F7D8DB9B847
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti52P → G in AAA40150 (PubMed:1714905).Curated1
Sequence conflicti60Q → T in AAA40150 (PubMed:1714905).Curated1
Sequence conflicti87S → C in AAA40150 (PubMed:1714905).Curated1
Sequence conflicti144T → I in AAA39885 (PubMed:1351683).Curated1
Sequence conflicti281 – 282EH → DR in AAA39885 (PubMed:1351683).Curated2
Sequence conflicti510K → E in AAA40150 (PubMed:1714905).Curated1
Sequence conflicti512 – 515RNTC → KHMLGPF in AAA40150 (PubMed:1714905).Curated4

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M65029 mRNA. Translation: AAA40150.1.
M93567 mRNA. Translation: AAA39885.1.
U09928
, U09914, U09915, U09916, U09917, U09918, U09919, U09920, U09921, U09922, U09923, U09924, U09925, U09926, U09927 Genomic DNA. Translation: AAC24729.1.
AK028602 mRNA. Translation: BAC26027.1.
CCDSiCCDS28980.1.
PIRiA59309.
RefSeqiNP_035293.1. NM_011163.4.
UniGeneiMm.378990.

Genome annotation databases

EnsembliENSMUST00000024884; ENSMUSP00000024884; ENSMUSG00000024079.
GeneIDi19106.
KEGGimmu:19106.
UCSCiuc008dph.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M65029 mRNA. Translation: AAA40150.1.
M93567 mRNA. Translation: AAA39885.1.
U09928
, U09914, U09915, U09916, U09917, U09918, U09919, U09920, U09921, U09922, U09923, U09924, U09925, U09926, U09927 Genomic DNA. Translation: AAC24729.1.
AK028602 mRNA. Translation: BAC26027.1.
CCDSiCCDS28980.1.
PIRiA59309.
RefSeqiNP_035293.1. NM_011163.4.
UniGeneiMm.378990.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1X48NMR-A96-170[»]
1X49NMR-A1-84[»]
ProteinModelPortaliQ03963.
SMRiQ03963.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-41411N.
IntActiQ03963. 2 interactors.
MINTiMINT-270896.
STRINGi10090.ENSMUSP00000024884.

Chemistry databases

ChEMBLiCHEMBL1795121.

PTM databases

iPTMnetiQ03963.
PhosphoSitePlusiQ03963.

Proteomic databases

EPDiQ03963.
MaxQBiQ03963.
PaxDbiQ03963.
PeptideAtlasiQ03963.
PRIDEiQ03963.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000024884; ENSMUSP00000024884; ENSMUSG00000024079.
GeneIDi19106.
KEGGimmu:19106.
UCSCiuc008dph.2. mouse.

Organism-specific databases

CTDi5610.
MGIiMGI:1353449. Eif2ak2.

Phylogenomic databases

eggNOGiKOG1033. Eukaryota.
ENOG410XS0B. LUCA.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000234351.
HOVERGENiHBG051430.
InParanoidiQ03963.
KOiK16195.
OMAiELLYICP.
OrthoDBiEOG091G088F.
PhylomeDBiQ03963.
TreeFamiTF317576.

Miscellaneous databases

EvolutionaryTraceiQ03963.
PROiQ03963.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000024079.
GenevisibleiQ03963. MM.

Family and domain databases

Gene3Di3.30.160.20. 2 hits.
InterProiIPR014720. dsRBD_dom.
IPR011009. Kinase-like_dom.
IPR033366. PKR.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR11042:SF102. PTHR11042:SF102. 1 hit.
PfamiPF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00358. DSRM. 2 hits.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50137. DS_RBD. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiE2AK2_MOUSE
AccessioniPrimary (citable) accession number: Q03963
Secondary accession number(s): Q61742, Q62026
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: November 1, 1997
Last modified: November 2, 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

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. 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.