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Q63184

- E2AK2_RAT

UniProt

Q63184 - E2AK2_RAT

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Protein

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

Gene

Eif2ak2

Organism
Rattus norvegicus (Rat)
Status
Reviewed - 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 and induction of cytokines and chemokines (By similarity). Plays a role in cortex-dependent memory consolidation.By similarity1 Publication

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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei265 – 2651ATPPROSITE-ProRule annotation
Active sitei373 – 3731Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi242 – 2509ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC
  3. protein kinase activity Source: UniProtKB
  4. protein serine/threonine kinase activity Source: UniProtKB-KW
  5. RNA binding Source: UniProtKB-KW

GO - Biological processi

  1. activation of MAPKK activity Source: UniProtKB
  2. defense response to virus Source: UniProtKB-KW
  3. innate immune response Source: UniProtKB-KW
  4. negative regulation of osteoblast proliferation Source: UniProtKB
  5. negative regulation of translation Source: UniProtKB
  6. negative regulation of viral genome replication Source: UniProtKB
  7. positive regulation of apoptotic process Source: RGD
  8. positive regulation of chemokine production Source: UniProtKB
  9. positive regulation of cytokine production Source: UniProtKB
  10. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  11. positive regulation of NIK/NF-kappaB signaling Source: UniProtKB
  12. positive regulation of stress-activated MAPK cascade Source: UniProtKB
  13. protein autophosphorylation Source: UniProtKB
  14. protein phosphorylation Source: UniProtKB
  15. regulation of hematopoietic progenitor cell differentiation Source: UniProtKB
  16. regulation of hematopoietic stem cell differentiation Source: UniProtKB
  17. regulation of hematopoietic stem cell proliferation Source: UniProtKB
  18. regulation of NLRP3 inflammasome complex assembly Source: UniProtKB
  19. response to exogenous dsRNA Source: RGD
  20. response to interferon-alpha Source: UniProtKB
  21. response to lipopolysaccharide Source: RGD
  22. response to mechanical stimulus Source: RGD
  23. response to organic substance Source: RGD
  24. response to toxic substance Source: RGD
  25. response to virus Source: UniProtKB
  26. response to vitamin E Source: RGD
  27. transcription, DNA-templated Source: UniProtKB-KW
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
Protein kinase RNA-activated
Short name:
PKR
Tyrosine-protein kinase EIF2AK2 (EC:2.7.10.2)
Gene namesi
Name:Eif2ak2
Synonyms:Prkr
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Unplaced

Organism-specific databases

RGDi3402. Eif2ak2.

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity. Cytoplasmperinuclear region By similarity

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. nucleus Source: RGD
  3. perinuclear region of cytoplasm Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 513512Interferon-induced, double-stranded RNA-activated protein kinasePRO_0000274915Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanineBy similarity
Cross-linki68 – 68Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
Modified residuei82 – 821PhosphoserineBy similarity
Modified residuei96 – 961Phosphotyrosine; by autocatalysisBy similarity
Cross-linki154 – 154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
Modified residuei157 – 1571Phosphotyrosine; by autocatalysisBy similarity
Modified residuei262 – 2621Phosphotyrosine; by autocatalysisBy similarity
Modified residuei406 – 4061Phosphothreonine; by autocatalysisBy similarity
Modified residuei411 – 4111Phosphothreonine; by autocatalysisBy similarity
Modified residuei416 – 4161PhosphoserineBy similarity

Post-translational modificationi

Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-411 is dependent on Thr-406 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

PRIDEiQ63184.

Expressioni

Inductioni

By type I interferons.By similarity

Gene expression databases

GenevestigatoriQ63184.

Interactioni

Subunit structurei

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

Protein-protein interaction databases

BioGridi248507. 1 interaction.
MINTiMINT-4569424.

Structurei

3D structure databases

ProteinModelPortaliQ63184.
SMRiQ63184. Positions 1-176, 226-502.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini8 – 7669DRBM 1PROSITE-ProRule annotationAdd
BLAST
Domaini95 – 16268DRBM 2PROSITE-ProRule annotationAdd
BLAST
Domaini236 – 502267Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni235 – 513279Interaction with TRAF5By similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi161 – 19434Ser-richAdd
BLAST

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

HOVERGENiHBG051430.
InParanoidiQ63184.
KOiK16195.
PhylomeDBiQ63184.

Family and domain databases

Gene3Di3.30.160.20. 2 hits.
InterProiIPR014720. dsRNA-bd_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00358. DSRM. 2 hits.
[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.

Q63184-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MASDTPGFYV DKLNKYSQIH KVKIIYKEIS VTGPPHDRRF TFQVIIEERE
60 70 80 90 100
FPEGEGRSKQ EAKNNAAKLA VEILDNENKV DSHTDASEQG LIEGNYIGLV
110 120 130 140 150
NSFAQKENLP VNFELCDPDS QLPHRFICKC KIGQTTYGTG FGANKKEAKQ
160 170 180 190 200
LAAKNAYQKL SEKSPSKTGF VTSLSSDFSS SSSITSNSAS QSASGRDFED
210 220 230 240 250
IFMNGLREKR KSGVKVPSDD VLRNKYTLDD RFSKDFEDIE EIGSGGFGQV
260 270 280 290 300
FKAKHRIDGK TYAIKRITYN TKKAKREVQA LAELNHANIV QYRVCWEGED
310 320 330 340 350
YDYDPENSTN GDTSRYKTRC LFIQMEFCDK GTLQQWLEKR NRSQEDKALV
360 370 380 390 400
LELFEQIVTG VDYIHSKGLI HRDLKPGNIF LVDEKHIKIG DFGLATALEN
410 420 430 440 450
DGNPRTKYTG TPQYMSPEQK SSLVEYGKEV DIFALGLILA ELLHICKTDS
460 470 480 490 500
EKIEFFQLLR NGIFSDDIFD NKEKSLLQKL LSSKPRERPN TSEILKTLAE
510
WKNISEKKKR NTC
Length:513
Mass (Da):58,259
Last modified:November 1, 1996 - v1
Checksum:i716751E84B7FED88
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L29281 mRNA. Translation: AAA61926.1.
PIRiS50216.
RefSeqiNP_062208.1. NM_019335.1.
UniGeneiRn.10022.

Genome annotation databases

GeneIDi54287.
KEGGirno:54287.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L29281 mRNA. Translation: AAA61926.1 .
PIRi S50216.
RefSeqi NP_062208.1. NM_019335.1.
UniGenei Rn.10022.

3D structure databases

ProteinModelPortali Q63184.
SMRi Q63184. Positions 1-176, 226-502.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 248507. 1 interaction.
MINTi MINT-4569424.

Proteomic databases

PRIDEi Q63184.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 54287.
KEGGi rno:54287.

Organism-specific databases

CTDi 5610.
RGDi 3402. Eif2ak2.

Phylogenomic databases

HOVERGENi HBG051430.
InParanoidi Q63184.
KOi K16195.
PhylomeDBi Q63184.

Miscellaneous databases

NextBioi 610880.
PROi Q63184.

Gene expression databases

Genevestigatori Q63184.

Family and domain databases

Gene3Di 3.30.160.20. 2 hits.
InterProi IPR014720. dsRNA-bd_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00358. DSRM. 2 hits.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS50137. DS_RBD. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Cloning and characterization of a cDNA encoding rat PKR, the double-stranded RNA-dependent eukaryotic initiation factor-2 kinase."
    Mellor H., Flowers K.M., Kimball S.R., Jefferson L.S.
    Biochim. Biophys. Acta 1219:693-696(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
    Tissue: Brain.
  2. "A new double-stranded RNA-binding protein that interacts with PKR."
    Coolidge C.J., Patton J.G.
    Nucleic Acids Res. 28:1407-1417(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH STRBP.
  3. "Blocking the eIF2? kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory."
    Stern E., Chinnakkaruppan A., David O., Sonenberg N., Rosenblum K.
    J. Neurosci. 33:2517-2525(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiE2AK2_RAT
AccessioniPrimary (citable) accession number: Q63184
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 6, 2007
Last sequence update: November 1, 1996
Last modified: October 29, 2014
This is version 100 of the entry and version 1 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. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3