E2AK2_RAT
ID E2AK2_RAT Reviewed; 513 AA.
AC Q63184;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Interferon-induced, double-stranded RNA-activated protein kinase;
DE EC=2.7.11.1;
DE AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 2;
DE Short=eIF-2A protein kinase 2;
DE AltName: Full=Interferon-inducible RNA-dependent protein kinase;
DE AltName: Full=Protein kinase RNA-activated;
DE Short=PKR;
DE Short=Protein kinase R {ECO:0000305};
DE AltName: Full=Tyrosine-protein kinase EIF2AK2;
DE EC=2.7.10.2;
GN Name=Eif2ak2; Synonyms=Prkr;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=7948027; DOI=10.1016/0167-4781(94)90229-1;
RA Mellor H., Flowers K.M., Kimball S.R., Jefferson L.S.;
RT "Cloning and characterization of a cDNA encoding rat PKR, the double-
RT stranded RNA-dependent eukaryotic initiation factor-2 kinase.";
RL Biochim. Biophys. Acta 1219:693-696(1994).
RN [2]
RP INTERACTION WITH STRBP.
RX PubMed=10684936; DOI=10.1093/nar/28.6.1407;
RA Coolidge C.J., Patton J.G.;
RT "A new double-stranded RNA-binding protein that interacts with PKR.";
RL Nucleic Acids Res. 28:1407-1417(2000).
CC -!- FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase
CC that phosphorylates the alpha subunit of eukaryotic translation
CC initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the
CC innate immune response to viral infection (By similarity). Inhibits
CC viral replication via the integrated stress response (ISR): EIF2S1/eIF-
CC 2-alpha phosphorylation in response to viral infection converts
CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting
CC to a shutdown of cellular and viral protein synthesis, while
CC concomitantly initiating the preferential translation of ISR-specific
CC mRNAs, such as the transcriptional activator ATF4 (By similarity).
CC Exerts its antiviral activity on a wide range of DNA and RNA viruses
CC (By similarity). Also involved in the regulation of signal
CC transduction, apoptosis, cell proliferation and differentiation:
CC phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3
CC and IRS1 (By similarity). In addition to serine/threonine-protein
CC kinase activity, also has tyrosine-protein kinase activity and
CC phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its
CC ubiquitination and proteosomal degradation (By similarity). Either as
CC an adapter protein and/or via its kinase activity, can regulate various
CC signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling
CC pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3)
CC involved in the expression of genes encoding pro-inflammatory cytokines
CC and IFNs (By similarity). Activates the NF-kappa-B pathway via
CC interaction with IKBKB and TRAF family of proteins and activates the
CC p38 MAP kinase pathway via interaction with MAP2K6 (By similarity). Can
CC act as both a positive and negative regulator of the insulin signaling
CC pathway (ISP) (By similarity). Negatively regulates ISP by inducing the
CC inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at
CC 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A
CC which activates FOXO1, which in turn up-regulates the expression of
CC insulin receptor substrate 2 (IRS2) (By similarity). Can regulate NLRP3
CC inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and
CC NLRC4 inflammasomes (By similarity). Plays a role in the regulation of
CC the cytoskeleton by binding to gelsolin (GSN), sequestering the protein
CC in an inactive conformation away from actin (By similarity).
CC {ECO:0000250|UniProtKB:P19525, ECO:0000250|UniProtKB:Q03963}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};
CC -!- ACTIVITY REGULATION: Initially produced in an inactive form and is
CC activated by binding to viral dsRNA, which causes dimerization and
CC autophosphorylation in the activation loop and stimulation of function.
CC ISGylation can activate it in the absence of viral infection. Can also
CC be activated by heparin, pro-inflammatory stimuli, growth factors,
CC cytokines, oxidative stress and the cellular protein PRKRA. Activity is
CC markedly stimulated by manganese ions. Activation is blocked by the
CC cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR (By similarity).
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with DNAJC3 (By
CC similarity). Interacts with STRBP. Forms a complex with FANCA, FANCC,
CC FANCG and HSP70 (By similarity). Interacts with ADAR/ADAR1 (By
CC similarity). The inactive form interacts with NCK1 and GSN. Interacts
CC (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2
CC (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with
CC MAP2K6, IKBKB/IKKB, IRS1, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2.
CC Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts
CC with DHX9 (via N-terminus) and this interaction is dependent upon
CC activation of the kinase (By similarity).
CC {ECO:0000250|UniProtKB:P19525, ECO:0000250|UniProtKB:Q03963}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P19525}. Nucleus
CC {ECO:0000250|UniProtKB:P19525}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues.
CC Autophosphorylation of Thr-411 is dependent on Thr-406 and is
CC stimulated by dsRNA binding and dimerization. Autophosphorylation
CC apparently leads to the activation of the kinase. Tyrosine
CC autophosphorylation is essential for efficient dsRNA-binding,
CC dimerization, and kinase activation (By similarity).
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; L29281; AAA61926.1; -; mRNA.
DR PIR; S50216; S50216.
DR RefSeq; NP_062208.1; NM_019335.1.
DR AlphaFoldDB; Q63184; -.
DR SMR; Q63184; -.
DR BioGRID; 248507; 3.
DR STRING; 10116.ENSRNOP00000067694; -.
DR jPOST; Q63184; -.
DR PaxDb; Q63184; -.
DR PRIDE; Q63184; -.
DR GeneID; 54287; -.
DR KEGG; rno:54287; -.
DR CTD; 5610; -.
DR RGD; 3402; Eif2ak2.
DR eggNOG; KOG1033; Eukaryota.
DR InParanoid; Q63184; -.
DR OrthoDB; 1195366at2759; -.
DR PhylomeDB; Q63184; -.
DR Reactome; R-RNO-1169408; ISG15 antiviral mechanism.
DR PRO; PR:Q63184; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003725; F:double-stranded RNA binding; ISO:RGD.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISO:RGD.
DR GO; GO:0051607; P:defense response to virus; ISO:RGD.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISO:RGD.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; ISS:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; ISS:UniProtKB.
DR GO; GO:0045071; P:negative regulation of viral genome replication; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
DR GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB.
DR GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEP:RGD.
DR GO; GO:0035455; P:response to interferon-alpha; ISS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:RGD.
DR GO; GO:0009612; P:response to mechanical stimulus; IEP:RGD.
DR GO; GO:0010033; P:response to organic substance; IEP:RGD.
DR GO; GO:0009636; P:response to toxic substance; IMP:RGD.
DR GO; GO:0009615; P:response to virus; ISS:UniProtKB.
DR GO; GO:0033197; P:response to vitamin E; IPI:RGD.
DR GO; GO:0006412; P:translation; ISO:RGD.
DR CDD; cd19903; DSRM_EIF2AK2_rpt1; 1.
DR InterPro; IPR014720; dsRBD_dom.
DR InterPro; IPR044452; EIF2AK2_DSRM_1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00035; dsrm; 2.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00358; DSRM; 2.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50137; DS_RBD; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Acetylation; Antiviral defense; ATP-binding; Cytoplasm; Immunity;
KW Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; RNA-binding;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Tyrosine-protein kinase; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CHAIN 2..513
FT /note="Interferon-induced, double-stranded RNA-activated
FT protein kinase"
FT /id="PRO_0000274915"
FT DOMAIN 8..76
FT /note="DRBM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 95..162
FT /note="DRBM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 236..502
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 235..513
FT /note="Interaction with TRAF5"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT ACT_SITE 373
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 242..250
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 265
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 82
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 84
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 96
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 157
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 227
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 262
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 406
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 411
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 416
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CROSSLNK 68
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CROSSLNK 154
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:P19525"
SQ SEQUENCE 513 AA; 58259 MW; 716751E84B7FED88 CRC64;
MASDTPGFYV DKLNKYSQIH KVKIIYKEIS VTGPPHDRRF TFQVIIEERE FPEGEGRSKQ
EAKNNAAKLA VEILDNENKV DSHTDASEQG LIEGNYIGLV NSFAQKENLP VNFELCDPDS
QLPHRFICKC KIGQTTYGTG FGANKKEAKQ LAAKNAYQKL SEKSPSKTGF VTSLSSDFSS
SSSITSNSAS QSASGRDFED IFMNGLREKR KSGVKVPSDD VLRNKYTLDD RFSKDFEDIE
EIGSGGFGQV FKAKHRIDGK TYAIKRITYN TKKAKREVQA LAELNHANIV QYRVCWEGED
YDYDPENSTN GDTSRYKTRC LFIQMEFCDK GTLQQWLEKR NRSQEDKALV LELFEQIVTG
VDYIHSKGLI HRDLKPGNIF LVDEKHIKIG DFGLATALEN DGNPRTKYTG TPQYMSPEQK
SSLVEYGKEV DIFALGLILA ELLHICKTDS EKIEFFQLLR NGIFSDDIFD NKEKSLLQKL
LSSKPRERPN TSEILKTLAE WKNISEKKKR NTC
