Q63184 (E2AK2_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 96. History...
Names and origin
|Protein names||Recommended name:|
Interferon-induced, double-stranded RNA-activated protein kinase
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
Tyrosine-protein kinase EIF2AK2
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||513 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
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.
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
By type I interferons By similarity.
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.
Contains 2 DRBM (double-stranded RNA-binding) domains.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 513||512||Interferon-induced, double-stranded RNA-activated protein kinase||PRO_0000274915|
|Domain||8 – 76||69||DRBM 1|
|Domain||95 – 162||68||DRBM 2|
|Domain||236 – 502||267||Protein kinase|
|Nucleotide binding||242 – 250||9||ATP By similarity|
|Region||235 – 513||279||Interaction with TRAF5 By similarity|
|Compositional bias||161 – 194||34||Ser-rich|
|Active site||373||1||Proton acceptor By similarity|
|Binding site||265||1||ATP By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylalanine By similarity|
|Modified residue||82||1||Phosphoserine By similarity|
|Modified residue||96||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||157||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||262||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||406||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||411||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||416||1||Phosphoserine By similarity|
|Cross-link||68||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity|
|Cross-link||154||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity|
|||"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].
|||"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.
|||"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.|
|L29281 mRNA. Translation: AAA61926.1.|
|RefSeq||NP_062208.1. NM_019335.1. |
3D structure databases
|SMR||Q63184. Positions 1-176, 226-502. |
Protein-protein interaction databases
|BioGrid||248507. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|RGD||3402. Eif2ak2. |
Gene expression databases
Family and domain databases
|Gene3D||22.214.171.124. 2 hits. |
|InterPro||IPR014720. dsRNA-bd_dom. |
|Pfam||PF00035. dsrm. 2 hits. |
PF00069. Pkinase. 1 hit.
|SMART||SM00358. DSRM. 2 hits. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS50137. DS_RBD. 2 hits. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: Q63184|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families