Interferon-induced, double-stranded RNA-activated protein kinase

UniProt P19525 Organism Homo sapiens Gene EIF2AK2, PKR, PRKR EC 2.7.11.1, 2.7.10.2

Also known as: EIF2AK2, PKR, PRKR

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. 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. 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). 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. 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. 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. 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. 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).

Classification

Family (Pfam): PF00035 dsrm, PF00069 Pkinase
InterPro: CC_SR_Kinase, dsRBD_dom, EIF2AK2_DSRM_1, EIF2AK2_DSRM_2, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS
Functional cluster: Serine/Threonine Protein Kinases

Experimental structures · PDB · 12

1QU6 NMR
2A19 X-ray 2.50A
2A1A X-ray 2.80A
3UIU X-ray 2.90A
6D3K X-ray 2.60A
6D3L X-ray 3.10A
7OBK X-ray 1.80A
7OBL X-ray 1.80A
8BI7 X-ray 1.40A
8I9J EM 6.39A
8IZN EM 6.67A
8QEL X-ray 2.45A

A predicted model is available from AlphaFold.

Gene Ontology · 40

Disease associations

leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome MONDO:0030035
dystonia 33 MONDO:0030513

Neighborhood · nearest proteins

Nearest neighbours of Interferon-induced, double-stranded RNA-activated protein kinase: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Interferon-induced, double-stranded RNA-activated protein kinase 8 shared papers
Protein TRS1 1 shared papers
Genome polyprotein 3 shared papers
Viral IRF2-like protein 1 shared papers
Protein K3 1 shared papers
Non-structural protein NS-S 1 shared papers
Genome polyprotein 2 shared papers
DnaJ homolog subfamily C member 3 1 shared papers
RNA-binding protein OPG065 1 shared papers
Non-structural protein 1 1 shared papers
Accessory factor US11 1 shared papers
Genome polyprotein 1 shared papers

Literature · 85 cited papers

Heterozygous EIF2AK2 Variant Causes Adolescence-Onset Generalized Dystonia Partially Responsive to DBS. Mov. Disord. Clin. Pract. · 2022
A Recurrent EIF2AK2 Missense Variant Causes Autosomal-Dominant Isolated Dystonia. Ann. Neurol. · 2021
EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia. Ann. Neurol. · 2021
De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am. J. Hum. Genet. · 2020
Structural Basis of Protein Kinase R Autophosphorylation. Biochemistry · 2019
KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation. PLoS Pathog. · 2017
A Single Amino Acid Dictates Protein Kinase R Susceptibility to Unrelated Viral Antagonists. PLoS Pathog. · 2016
Moco biosynthesis and the ATAC acetyltransferase engage translation initiation by inhibiting latent PKR activity. J. Mol. Cell Biol. · 2016
Mutational analysis of vaccinia virus E3 protein: the biological functions do not correlate with its biochemical capacity to bind double-stranded RNA. J. Virol. · 2015
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
PKR regulates proliferation, differentiation and survival of murine hematopoietic stem/progenitor cells. Blood · 2013
The modulation of hepatitis C virus 1a replication by PKR is dependent on NF-kB mediated interferon beta response in Huh7.5.1 cells. Virology · 2013
… and 73 more in the literature graph

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