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Q63184

- E2AK2_RAT

UniProt

Q63184 - E2AK2_RAT

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
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    • History
      Entry version 99 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    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 binding Source: RGD
    4. protein kinase activity Source: UniProtKB
    5. protein serine/threonine kinase activity Source: UniProtKB-KW
    6. 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

    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

    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.
    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

    MASDTPGFYV DKLNKYSQIH KVKIIYKEIS VTGPPHDRRF TFQVIIEERE    50
    FPEGEGRSKQ EAKNNAAKLA VEILDNENKV DSHTDASEQG LIEGNYIGLV 100
    NSFAQKENLP VNFELCDPDS QLPHRFICKC KIGQTTYGTG FGANKKEAKQ 150
    LAAKNAYQKL SEKSPSKTGF VTSLSSDFSS SSSITSNSAS QSASGRDFED 200
    IFMNGLREKR KSGVKVPSDD VLRNKYTLDD RFSKDFEDIE EIGSGGFGQV 250
    FKAKHRIDGK TYAIKRITYN TKKAKREVQA LAELNHANIV QYRVCWEGED 300
    YDYDPENSTN GDTSRYKTRC LFIQMEFCDK GTLQQWLEKR NRSQEDKALV 350
    LELFEQIVTG VDYIHSKGLI HRDLKPGNIF LVDEKHIKIG DFGLATALEN 400
    DGNPRTKYTG TPQYMSPEQK SSLVEYGKEV DIFALGLILA ELLHICKTDS 450
    EKIEFFQLLR NGIFSDDIFD NKEKSLLQKL LSSKPRERPN TSEILKTLAE 500
    WKNISEKKKR NTC 513
    Length:513
    Mass (Da):58,259
    Last modified:November 1, 1996 - v1
    Checksum:i716751E84B7FED88
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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.
    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 1, 2014
    This is version 99 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