CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-004783
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Interferon-induced, double-stranded RNA-activated protein kinase 
Protein Synonyms/Alias
 Eukaryotic translation initiation factor 2-alpha kinase 2; eIF-2A protein kinase 2; Interferon-inducible RNA-dependent protein kinase; P1/eIF-2A protein kinase; Protein kinase RNA-activated; PKR; Tyrosine-protein kinase EIF2AK2; p68 kinase 
Gene Name
 EIF2AK2 
Gene Synonyms/Alias
 PKR; PRKR 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
253RFDLPDMKETKYTVDubiquitination[1]
268KRFGMDFKEIELIGSubiquitination[2]
299TYVIKRVKYNNEKAEubiquitination[2]
400ELFEQITKGVDYIHSubiquitination[2]
416KLIHRDLKPSNIFLVubiquitination[1]
426NIFLVDTKQVKIGDFubiquitination[2]
440FGLVTSLKNDGKRTRubiquitination[1]
509IISDIFDKKEKTLLQubiquitination[1]
510ISDIFDKKEKTLLQKubiquitination[1]
517KEKTLLQKLLSKKPEubiquitination[1, 3, 4]
541RTLTVWKKSPEKNERubiquitination[1]
Reference
 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [4] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789] 
Functional Description
 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 hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). 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, IRS1 and the HHV-1 viral protein US11. 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. 
Sequence Annotation
 DOMAIN 9 77 DRBM 1.
 DOMAIN 100 167 DRBM 2.
 DOMAIN 267 538 Protein kinase.
 REPEAT 331 343 1.
 REPEAT 345 357 2.
 NP_BIND 273 281 ATP (By similarity).
 REGION 266 551 Interaction with TRAF5.
 REGION 331 357 2 X 13 AA approximate repeats.
 ACT_SITE 414 414 Proton acceptor (By similarity).
 BINDING 296 296 ATP.
 MOD_RES 2 2 N-acetylalanine.
 MOD_RES 83 83 Phosphoserine.
 MOD_RES 88 88 Phosphothreonine; by autocatalysis
 MOD_RES 89 89 Phosphothreonine; by autocatalysis
 MOD_RES 90 90 Phosphothreonine; by autocatalysis
 MOD_RES 101 101 Phosphotyrosine; by autocatalysis.
 MOD_RES 162 162 Phosphotyrosine; by autocatalysis.
 MOD_RES 242 242 Phosphoserine; by autocatalysis
 MOD_RES 255 255 Phosphothreonine; by autocatalysis
 MOD_RES 258 258 Phosphothreonine; by autocatalysis
 MOD_RES 293 293 Phosphotyrosine; by autocatalysis.
 MOD_RES 446 446 Phosphothreonine; by autocatalysis.
 MOD_RES 451 451 Phosphothreonine; by autocatalysis.
 MOD_RES 456 456 Phosphoserine.
 CROSSLNK 69 69 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 159 159 Glycyl lysine isopeptide (Lys-Gly)  
Keyword
 3D-structure; Acetylation; Alternative splicing; Antiviral defense; ATP-binding; Complete proteome; Cytoplasm; Direct protein sequencing; Host-virus interaction; Immunity; Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat; RNA-binding; Serine/threonine-protein kinase; Transcription; Transcription regulation; Transferase; Tyrosine-protein kinase; Ubl conjugation. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 551 AA 
Protein Sequence
MAGDLSAGFF MEELNTYRQK QGVVLKYQEL PNSGPPHDRR FTFQVIIDGR EFPEGEGRSK 60
KEAKNAAAKL AVEILNKEKK AVSPLLLTTT NSSEGLSMGN YIGLINRIAQ KKRLTVNYEQ 120
CASGVHGPEG FHYKCKMGQK EYSIGTGSTK QEAKQLAAKL AYLQILSEET SVKSDYLSSG 180
SFATTCESQS NSLVTSTLAS ESSSEGDFSA DTSEINSNSD SLNSSSLLMN GLRNNQRKAK 240
RSLAPRFDLP DMKETKYTVD KRFGMDFKEI ELIGSGGFGQ VFKAKHRIDG KTYVIKRVKY 300
NNEKAEREVK ALAKLDHVNI VHYNGCWDGF DYDPETSDDS LESSDYDPEN SKNSSRSKTK 360
CLFIQMEFCD KGTLEQWIEK RRGEKLDKVL ALELFEQITK GVDYIHSKKL IHRDLKPSNI 420
FLVDTKQVKI GDFGLVTSLK NDGKRTRSKG TLRYMSPEQI SSQDYGKEVD LYALGLILAE 480
LLHVCDTAFE TSKFFTDLRD GIISDIFDKK EKTLLQKLLS KKPEDRPNTS EILRTLTVWK 540
KSPEKNERHT C 551 
Gene Ontology
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0003725; F:double-stranded RNA binding; TAS:ProtInc.
 GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; TAS:ProtInc.
 GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:EC.
 GO:0008601; F:protein phosphatase type 2A regulator activity; TAS:ProtInc.
 GO:0000186; P:activation of MAPKK activity; IMP:UniProtKB.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Compara.
 GO:0030683; P:evasion or tolerance by virus of host immune response; TAS:Reactome.
 GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
 GO:0019054; P:modulation by virus of host cellular process; TAS:Reactome.
 GO:0033689; P:negative regulation of osteoblast proliferation; IMP:UniProtKB.
 GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
 GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
 GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
 GO:1901224; P:positive regulation of NIK/NF-kappaB cascade; ISS:UniProtKB.
 GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB.
 GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
 GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB.
 GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
 GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB.
 GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
 GO:0035455; P:response to interferon-alpha; IDA:UniProtKB.
 GO:0009615; P:response to virus; IMP:UniProtKB.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0006412; P:translation; IEA:Compara.
 GO:0019058; P:viral infectious cycle; TAS:Reactome.
 GO:0006926; P:virus-infected cell apoptotic process; IEA:Compara. 
Interpro
 IPR001159; Ds-RNA-bd.
 IPR014720; dsRNA-bd-like_dom.
 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR008271; Ser/Thr_kinase_AS. 
Pfam
 PF00035; dsrm
 PF00069; Pkinase 
SMART
 SM00358; DSRM 
PROSITE
 PS50137; DS_RBD
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 
PRINTS