CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-011142
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; Serine/threonine-protein kinase TIK; Tyrosine-protein kinase EIF2AK2; p68 kinase 
Gene Name
 Eif2ak2 
Gene Synonyms/Alias
 Pkr; Prkr; Tik 
Created Date
 July 27, 2013 
Organism
 Mus musculus (Mouse) 
NCBI Taxa ID
 10090 
Lysine Modification
Position
Peptide
Type
References
378GLIHRDLKPGNIFLVubiquitination[1]
Reference
 [1] Proteomic analyses reveal divergent ubiquitylation site patterns in murine tissues.
 Wagner SA, Beli P, Weinert BT, Schölz C, Kelstrup CD, Young C, Nielsen ML, Olsen JV, Brakebusch C, Choudhary C.
 Mol Cell Proteomics. 2012 Dec;11(12):1578-85. [PMID: 22790023] 
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 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, induction of cytokines and chemokines and plays a role in cortex-dependent memory consolidation. 
Sequence Annotation
 DOMAIN 8 76 DRBM 1.
 DOMAIN 95 162 DRBM 2.
 DOMAIN 242 504 Protein kinase.
 NP_BIND 248 256 ATP (By similarity).
 REGION 241 515 Interaction with TRAF5 (By similarity).
 ACT_SITE 376 376 Proton acceptor (By similarity).
 BINDING 271 271 ATP (By similarity).
 MOD_RES 2 2 N-acetylalanine (By similarity).
 MOD_RES 96 96 Phosphotyrosine; by autocatalysis (By
 MOD_RES 157 157 Phosphotyrosine; by autocatalysis (By
 MOD_RES 268 268 Phosphotyrosine; by autocatalysis (By
 MOD_RES 409 409 Phosphothreonine; by autocatalysis (By
 MOD_RES 414 414 Phosphothreonine; by autocatalysis (By
 MOD_RES 419 419 Phosphoserine (By similarity).
 CROSSLNK 68 68 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 154 154 Glycyl lysine isopeptide (Lys-Gly)  
Keyword
 3D-structure; Acetylation; Antiviral defense; ATP-binding; Complete proteome; Cytoplasm; Immunity; Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; 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
 515 AA 
Protein Sequence
MASDTPGFYM DKLNKYRQMH GVAITYKELS TSGPPHDRRF TFQVLIDEKE FPEAKGRSKQ 60
EARNAAAKLA VDILDNENKV DCHTSASEQG LFVGNYIGLV NSFAQKKKLS VNYEQCEPNS 120
ELPQRFICKC KIGQTMYGTG SGVTKQEAKQ LAAKEAYQKL LKSPPKTAGT SSSVVTSTFS 180
GFSSSSSMTS NGVSQSAPGS FSSENVFTNG LGENKRKSGV KVSPDDVQRN KYTLDARFNS 240
DFEDIEEIGL GGFGQVFKAK HRIDGKRYAI KRVKYNTEKA EHEVQALAEL NHVNIVQYHS 300
CWEGVDYDPE HSMSDTSRYK TRCLFIQMEF CDKGTLEQWM RNRNQSKVDK ALILDLYEQI 360
VTGVEYIHSK GLIHRDLKPG NIFLVDERHI KIGDFGLATA LENDGKSRTR RTGTLQYMSP 420
EQLFLKHYGK EVDIFALGLI LAELLHTCFT ESEKIKFFES LRKGDFSNDI FDNKEKSLLK 480
KLLSEKPKDR PETSEILKTL AEWRNISEKK KRNTC 515 
Gene Ontology
 GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0003725; F:double-stranded RNA binding; IDA:MGI.
 GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:EC.
 GO:0004672; F:protein kinase activity; IMP:UniProtKB.
 GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
 GO:0000186; P:activation of MAPKK activity; ISS:UniProtKB.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:MGI.
 GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
 GO:0033689; P:negative regulation of osteoblast proliferation; ISS:UniProtKB.
 GO:0017148; P:negative regulation of translation; ISS:UniProtKB.
 GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
 GO:0032722; P:positive regulation of chemokine production; IMP:UniProtKB.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
 GO:1901224; P:positive regulation of NIK/NF-kappaB cascade; IMP:UniProtKB.
 GO:0032874; P:positive regulation of stress-activated MAPK cascade; IMP:UniProtKB.
 GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
 GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; IMP:UniProtKB.
 GO:1902036; P:regulation of hematopoietic stem cell differentiation; IMP:UniProtKB.
 GO:1902033; P:regulation of hematopoietic stem cell proliferation; IMP:UniProtKB.
 GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; IMP:UniProtKB.
 GO:0035455; P:response to interferon-alpha; ISS:UniProtKB.
 GO:0009615; P:response to virus; ISS:UniProtKB.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0006412; P:translation; IDA:MGI.
 GO:0006926; P:virus-infected cell apoptotic process; IDA:MGI. 
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