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Q63184 (E2AK2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 98. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Eif2ak2
Synonyms:Prkr
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length513 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation

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.

Subunit structure

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. Ref.2

Subcellular location

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

Induction

By type I interferons By similarity.

Post-translational modification

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.

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.

Contains 2 DRBM (double-stranded RNA-binding) domains.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processAntiviral defense
Immunity
Innate immunity
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   DomainRepeat
   LigandATP-binding
Nucleotide-binding
RNA-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
Tyrosine-protein kinase
   PTMAcetylation
Isopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of MAPKK activity

Inferred from sequence or structural similarity. Source: UniProtKB

defense response to virus

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of osteoblast proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of translation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of viral genome replication

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of NIK/NF-kappaB signaling

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of apoptotic process

Inferred from mutant phenotype PubMed 18535002. Source: RGD

positive regulation of chemokine production

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cytokine production

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of stress-activated MAPK cascade

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of NLRP3 inflammasome complex assembly

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of hematopoietic progenitor cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of hematopoietic stem cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of hematopoietic stem cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

response to exogenous dsRNA

Inferred from expression pattern PubMed 15920723. Source: RGD

response to interferon-alpha

Inferred from sequence or structural similarity. Source: UniProtKB

response to lipopolysaccharide

Inferred from mutant phenotype PubMed 15630703. Source: RGD

response to mechanical stimulus

Inferred from expression pattern PubMed 15781241. Source: RGD

response to organic substance

Inferred from expression pattern PubMed 17761171. Source: RGD

response to toxic substance

Inferred from mutant phenotype PubMed 18535002. Source: RGD

response to virus

Inferred from sequence or structural similarity. Source: UniProtKB

response to vitamin E

Inferred from physical interaction PubMed 17953670. Source: RGD

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from direct assay PubMed 17953670. Source: RGD

perinuclear region of cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

RNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

non-membrane spanning protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

protein binding

Inferred from physical interaction PubMed 17953670. Source: RGD

protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 513512Interferon-induced, double-stranded RNA-activated protein kinase
PRO_0000274915

Regions

Domain8 – 7669DRBM 1
Domain95 – 16268DRBM 2
Domain236 – 502267Protein kinase
Nucleotide binding242 – 2509ATP By similarity
Region235 – 513279Interaction with TRAF5 By similarity
Compositional bias161 – 19434Ser-rich

Sites

Active site3731Proton acceptor By similarity
Binding site2651ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue821Phosphoserine By similarity
Modified residue961Phosphotyrosine; by autocatalysis By similarity
Modified residue1571Phosphotyrosine; by autocatalysis By similarity
Modified residue2621Phosphotyrosine; by autocatalysis By similarity
Modified residue4061Phosphothreonine; by autocatalysis By similarity
Modified residue4111Phosphothreonine; by autocatalysis By similarity
Modified residue4161Phosphoserine By similarity
Cross-link68Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity
Cross-link154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity

Sequences

Sequence LengthMass (Da)Tools
Q63184 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 716751E84B7FED88

FASTA51358,259
        10         20         30         40         50         60 
MASDTPGFYV DKLNKYSQIH KVKIIYKEIS VTGPPHDRRF TFQVIIEERE FPEGEGRSKQ 

        70         80         90        100        110        120 
EAKNNAAKLA VEILDNENKV DSHTDASEQG LIEGNYIGLV NSFAQKENLP VNFELCDPDS 

       130        140        150        160        170        180 
QLPHRFICKC KIGQTTYGTG FGANKKEAKQ LAAKNAYQKL SEKSPSKTGF VTSLSSDFSS 

       190        200        210        220        230        240 
SSSITSNSAS QSASGRDFED IFMNGLREKR KSGVKVPSDD VLRNKYTLDD RFSKDFEDIE 

       250        260        270        280        290        300 
EIGSGGFGQV FKAKHRIDGK TYAIKRITYN TKKAKREVQA LAELNHANIV QYRVCWEGED 

       310        320        330        340        350        360 
YDYDPENSTN GDTSRYKTRC LFIQMEFCDK GTLQQWLEKR NRSQEDKALV LELFEQIVTG 

       370        380        390        400        410        420 
VDYIHSKGLI HRDLKPGNIF LVDEKHIKIG DFGLATALEN DGNPRTKYTG TPQYMSPEQK 

       430        440        450        460        470        480 
SSLVEYGKEV DIFALGLILA ELLHICKTDS EKIEFFQLLR NGIFSDDIFD NKEKSLLQKL 

       490        500        510 
LSSKPRERPN TSEILKTLAE WKNISEKKKR NTC 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L29281 mRNA. Translation: AAA61926.1.
PIRS50216.
RefSeqNP_062208.1. NM_019335.1.
UniGeneRn.10022.

3D structure databases

ProteinModelPortalQ63184.
SMRQ63184. Positions 1-176, 226-502.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid248507. 1 interaction.
MINTMINT-4569424.

Proteomic databases

PRIDEQ63184.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID54287.
KEGGrno:54287.

Organism-specific databases

CTD5610.
RGD3402. Eif2ak2.

Phylogenomic databases

HOVERGENHBG051430.
KOK16195.
PhylomeDBQ63184.

Gene expression databases

GenevestigatorQ63184.

Family and domain databases

Gene3D3.30.160.20. 2 hits.
InterProIPR014720. dsRNA-bd_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00358. DSRM. 2 hits.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50137. DS_RBD. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio610880.
PROQ63184.

Entry information

Entry nameE2AK2_RAT
AccessionPrimary (citable) accession number: Q63184
Entry history
Integrated into UniProtKB/Swiss-Prot: February 6, 2007
Last sequence update: November 1, 1996
Last modified: June 11, 2014
This is version 98 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families