EIF2AK2
entrez
5610
canonical
uniprot
P19525
canonical
ensembl
ENSG00000055332
resolver
ensp
ENSP00000233057
resolver
ensp
ENSP00000378559
resolver
ensp
ENSP00000385014
resolver
ensp
ENSP00000505772
resolver
ensp
ENSP00000506455
resolver
ensp
ENSP00000544677
resolver
ensp
ENSP00000619587
resolver
ensp
ENSP00000644778
resolver
enst
ENST00000679979
resolver
enst
ENST00000874618
resolver
enst
ENST00000949528
resolver
genesymbol
EIF2AK2
resolver
genesymbol_syn
PKR
resolver
genesymbol_syn
PRKR
resolver
hgnc
HGNC:9437
resolver
uniprot
A0A7P0Z4M0
resolver
uniprot
A8K3P0
resolver
uniprot
D6W584
resolver
uniprot
E9PC80
resolver
uniprot
Q52M43
resolver
uniprot
Q7Z6F6
resolver
uniprot
Q8IW76
resolver
uniprot
Q9UIR4
resolver
uniprot_entry
A0A7P0Z4M0_HUMAN
resolver
uniprot_entry
E2AK2_HUMAN
resolver
uniprot_entry
Q8IW76_HUMAN
resolver
uniprot_sec
A8K3P0
resolver
uniprot_sec
D6W584
resolver
uniprot_sec
E9PC80
resolver
uniprot_sec
Q52M43
resolver
uniprot_sec
Q7Z6F6
resolver
uniprot_sec
Q9UIR4
resolver
activity_regulation
ACTIVITY 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, pro-inflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans-activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}.
uniprot
proteins
amino_acid_sequence
MAGDLSAGFFMEELNTYRQKQGVVLKYQELPNSGPPHDRRFTFQVIIDGREFPEGEGRSKKEAKNAAAKLAVEILNKEKKAVSPLLLTTTNSSEGLSMGNYIGLINRIAQKKRLTVNYEQCASGVHGPEGFHYKCKMGQKEYSIGTGSTKQEAKQLAAKLAYLQILSEETSVKSDYLSSGSFATTCESQSNSLVTSTLASESSSEGDFSADTSEINSNSDSLNSSSLLMNGLRNNQRKAKRSLAPRFDLPDMKETKYTVDKRFGMDFKEIELIGSGGFGQVFKAKHRIDGKTYVIKRVKYNNEKAEREVKALAKLDHVNIVHYNGCWDGFDYDPETSDDSLESSDYDPENSKNSSRSKTKCLFIQMEFCDKGTLEQWIEKRRGEKLDKVLALELFEQITKGVDYIHSKKLIHRDLKPSNIFLVDTKQVKIGDFGLVTSLKNDGKRTRSKGTLRYMSPEQISSQDYGKEVDLYALGLILAELLHVCDTAFETSKFFTDLRDGIISDIFDKKEKTLLQKLLSKKPEDRPNTSEILRTLTVWKKSPEKNERHTC
uniprot
proteins
disease_involvement
DISEASE: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination. {ECO:0000269|PubMed:32197074}. Note=The disease may be caused by variants affecting the gene represented in this entry.; DISEASE: Dystonia 33 (DYT33) [MIM:619687]: A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT33 is a slowly progressive form characterized by onset of focal or generalized dystonia in the first decades of life. Disease manifestations are variable. Some patients show ambulation difficulties, dysarthria, or dysphagia. Some affected individuals may manifest motor delay, lower limb spasticity, and mild developmental delay with intellectual disability. DYT33 penetrance is incomplete. Inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:33236446, ECO:0000269|PubMed:33866603, ECO:0000269|PubMed:35146068}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.10.2
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:18835251, PubMed:19189853, PubMed:19507191, PubMed:21072047, PubMed:21123651, PubMed:22381929, PubMed:22948139, PubMed:23229543). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543). 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) (PubMed:11836380, PubMed:19189853, PubMed:19840259, PubMed:20171114, PubMed:21710204, PubMed:23115276, PubMed:23399035). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:19229320, PubMed:22214662). 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 proteasomal degradation (PubMed:20395957). 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 pro-inflammatory cytokines and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). 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 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959). 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) (PubMed:20685959). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity). {ECO:0000250|UniProtKB:Q03963, ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035, ECO:0000269|PubMed:32197074}.
uniprot
proteins
mass_dalton
62094
uniprot
proteins
mutagenesis
MUTAGEN 59..60; /note="SK->AA: In FL-PKR-2AI; moderate loss of activity but no effect on dsRNA binding."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 60; /note="K->A: Impairs dsRNA binding but not dimerization or activity."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 67; /note="A->E: Significant loss of activity; loss of dsRNA binding and dimerization."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 83; /note="S->A: No effect on enzymatic activity; when associated with A-88; A-89 and A-90."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 88; /note="T->A: No effect on enzymatic activity; when associated with A-83; A-89 and A-90."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 89; /note="T->A: No effect on enzymatic activity; when associated with A-83; A-88 and A-90."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 90; /note="T->A: No effect on enzymatic activity; when associated with A-83; A-88 and A-89."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 149..150; /note="TK->AA: In FL-PKR-2AII; no effect on activity."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 242; /note="S->A: Moderate loss of activity; when associated with A-255 and A-258."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 244..296; /note="Missing: Loss of activity."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 255; /note="T->A: Moderate loss of activity; when associated with A-242 and A-255."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 258; /note="T->A: Moderate loss of activity."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 296; /note="K->R: Loss of activity."; /evidence="ECO:0000269|PubMed:11152499"; MUTAGEN 446; /note="T->A: Significant loss of activity and impairs autophosphorylation of T-451."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 451; /note="T->A: Loss of activity."; /evidence="ECO:0000269|PubMed:11337501"; MUTAGEN 486; /note="D->V: 15-fold decrease in K3L binding affinity and thus resistance of mutated PKR to K3L inhibition."; /evidence="ECO:0000269|PubMed:18971339"; MUTAGEN 489; /note="F->S: Loss of PKR inhibition by HCMV protein TRS1."; /evidence="ECO:0000269|PubMed:27780231"; MUTAGEN 496; /note="T->K: No effect on PKR inhibition by HCMV protein TRS1."; /evidence="ECO:0000269|PubMed:27780231"; MUTAGEN 502; /note="I->T: No effect on PKR inhibition by HCMV protein TRS1."; /evidence="ECO:0000269|PubMed:27780231"; MUTAGEN 510; /note="K->R: No effect on PKR inhibition by HCMV protein TRS1."; /evidence="ECO:0000269|PubMed:27780231"; MUTAGEN 516; /note="Q->E: No effect on PKR inhibition by HCMV protein TRS1."; /evidence="ECO:0000269|PubMed:27780231
uniprot
proteins
post_translational_modification
PTM: Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 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. Autophosphorylation is inhibited by the concerted action of ATAC complex subunit MBIP and molybdopterin synthase complex subunit MOCS2B (PubMed:26705305). {ECO:0000269|PubMed:11152499, ECO:0000269|PubMed:11337501, ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:16373505, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}.
uniprot
proteins
protein_family
GCN2 subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
Ser/Thr protein kinase family
uniprot
proteins
pubmed
10390359
uniprot
proteins
pubmed
10848580
uniprot
proteins
pubmed
11152499
uniprot
proteins
pubmed
11160738
uniprot
proteins
pubmed
11337501
uniprot
proteins
pubmed
11438532
uniprot
proteins
pubmed
11836380
uniprot
proteins
pubmed
12882984
uniprot
proteins
pubmed
1373553
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15121867
uniprot
proteins
pubmed
15207627
uniprot
proteins
pubmed
15229216
uniprot
proteins
pubmed
15299030
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15815621
uniprot
proteins
pubmed
16179258
uniprot
proteins
pubmed
16373505
uniprot
proteins
pubmed
16951545
uniprot
proteins
pubmed
1695551
uniprot
proteins
pubmed
16987971
uniprot
proteins
pubmed
17079286
uniprot
proteins
pubmed
17158706
uniprot
proteins
pubmed
17196820
uniprot
proteins
pubmed
17267064
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17451199
uniprot
proteins
pubmed
18096616
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18835251
uniprot
proteins
pubmed
18971339
uniprot
proteins
pubmed
19189853
uniprot
proteins
pubmed
19229320
uniprot
proteins
pubmed
19507191
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
19840259
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20171114
uniprot
proteins
pubmed
20395957
uniprot
proteins
pubmed
20519500
uniprot
proteins
pubmed
20685959
uniprot
proteins
pubmed
21029237
uniprot
proteins
pubmed
21072047
uniprot
proteins
pubmed
21123651
uniprot
proteins
pubmed
21166592
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21710204
uniprot
proteins
pubmed
21924887
uniprot
proteins
pubmed
22214662
uniprot
proteins
pubmed
22223895
uniprot
proteins
pubmed
22381929
uniprot
proteins
pubmed
22633454
uniprot
proteins
pubmed
22801494
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
22948139
uniprot
proteins
pubmed
23084476
uniprot
proteins
pubmed
23092889
uniprot
proteins
pubmed
23115276
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23202496
uniprot
proteins
pubmed
23229543
uniprot
proteins
pubmed
23325696
uniprot
proteins
pubmed
23354059
uniprot
proteins
pubmed
23372823
uniprot
proteins
pubmed
23399035
uniprot
proteins
pubmed
23403623
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
25740987
uniprot
proteins
pubmed
26705305
uniprot
proteins
pubmed
27780231
uniprot
proteins
pubmed
29084250
uniprot
proteins
pubmed
31246429
uniprot
proteins
pubmed
32197074
uniprot
proteins
pubmed
33236446
uniprot
proteins
pubmed
33866603
uniprot
proteins
pubmed
35146068
uniprot
proteins
pubmed
8576172
uniprot
proteins
pubmed
8812437
uniprot
proteins
pubmed
8921913
uniprot
proteins
pubmed
9079663
uniprot
proteins
pubmed
9143277
uniprot
proteins
pubmed
9710605
uniprot
proteins
pubmed
9726442
uniprot
proteins
pubmed
9736623
uniprot
proteins
pubmed
9781815
uniprot
proteins
sequence_length
551
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:26705305}. Nucleus {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:15121867}. Note=Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt-Jakob disease patients. {ECO:0000269|PubMed:21072047}.
uniprot
proteins