Protein kinase R

EIF2AK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3UIU, 1QU6, 2A19, 2A1A
Identifiers
Aliases	EIF2AK2, EIF2AK1, PKR, PPP1R83, PRKR, eukaryotic translation initiation factor 2 alpha kinase 2
External IDs	OMIM: 176871 MGI: 1353449 HomoloGene: 48134 GeneCards: EIF2AK2
EC number	2.7.10.2
Targeted by Drug
PKR inhibitor[1]
Gene ontology Molecular function • transferase activity • protein kinase activity • nucleotide binding • non-membrane spanning protein tyrosine kinase activity • kinase activity • protein serine/threonine kinase activity • protein binding • RNA binding • double-stranded RNA binding • poly(A) RNA binding • protein phosphatase type 2A regulator activity • protein tyrosine kinase activity • ATP binding • eukaryotic translation initiation factor 2alpha kinase activity Cellular component • cytoplasm • cytosol • ribosome • membrane • perinuclear region of cytoplasm • nucleus Biological process • negative regulation of translation • regulation of hematopoietic stem cell proliferation • regulation of transcription, DNA-templated • translation • positive regulation of cytokine production • activation of MAPKK activity • immune system process • phosphorylation • cellular response to amino acid starvation • negative regulation of apoptotic process • evasion or tolerance by virus of host immune response • positive regulation of NIK/NF-kappaB signaling • transcription, DNA-templated • endoplasmic reticulum unfolded protein response • protein phosphorylation • negative regulation of viral genome replication • regulation of hematopoietic stem cell differentiation • regulation of hematopoietic progenitor cell differentiation • positive regulation of NF-kappaB transcription factor activity • defense response to virus • response to interferon-alpha • positive regulation of chemokine production • negative regulation of osteoblast proliferation • protein autophosphorylation • regulation of NLRP3 inflammasome complex assembly • peptidyl-tyrosine phosphorylation • innate immune response • viral process • response to toxic substance • positive regulation of stress-activated MAPK cascade • response to virus • regulation of protein phosphatase type 2A activity • regulation of translational initiation by eIF2 alpha phosphorylation • regulation of apoptotic process • negative regulation of cell proliferation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5610	19106
Ensembl	ENSG00000055332	ENSMUSG00000024079
UniProt	P19525	Q03963
RefSeq (mRNA)	NM_001135651 NM_001135652 NM_002759	NM_011163
RefSeq (protein)	NP_001129123.1 NP_001129124.1 NP_002750.1	NP_035293.1
Location (UCSC)	Chr 2: 37.1 – 37.16 Mb	Chr 17: 78.85 – 78.88 Mb
PubMed search	[2]	[3]
Wikidata

Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene.^[4][5]

PKR protects against viral infections.

Mechanism of action

Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. PKR can also be activated by the protein PACT or by heparin. PKR contains an N-terminal dsRNA binding domain (dsRBD) and a C-terminal kinase domain, that gives it pro-apoptotic (cell-killing) functions. The dsRBD consists of two tandem copies of a conserved double stranded RNA binding motif, dsRBM1 and dsRBM2. PKR is induced by interferon in a latent state. Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent auto-phosphorylation reactions. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein. Once active, PKR is able to phosphorylate the eukaryotic translation initiation factor eIF2α. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. Since ElF2α is involved in the commonly initiation translation from an AUG codon, the alternative non-AUG initiation takes place instead. An example of mRNAs using non-AUG initiation are mRNAs for the heat shock proteins. Active PKR is also able to mediate the activation of the transcription factor NFkB, by phosphorylating its inhibitory subunit, IkB. Activated NFkB upregulates the expression of Interferon cytokines, which work to spread the antiviral signal locally. Active PKR is also able to activate tumor suppressor PP2A which regulates the cell cycle and the metabolism. Through complex mechanisms, active PKR is also able to induce cellular apoptosis, to prevent further viral spread.

PKR stress pathway

PKR is in the center of cellular response to different stress signals such as pathogens, lack of nutrients, cytokines, irradiation, mechanical stress or stress of endoplasmic reticulum (ER). PKR pathway leads to stress response through activation of other stress pathway such as JNK, p38, NFkB, PP2A and phosphorylation of eIF2α. ER stress caused by excess of unfolded proteins leads to inflammatory responses. PKR contributes to this response by interacting with several inflammatory kinases such as IKK, JNK, ElF2α, insulin receptor and others. This metabolically activated inflammatory complex is called metabolic inflammasome or metaflammasome.^[6][7]

Viral defense

Viruses have developed many mechanisms to counteract the PKR mechanism. It may be done by Decoy dsRNA, degradation, hiding of virus dsRNA, dimerization block, dephosphorylation of substrate or by a pseudosubstrate.

For instance, Epstein-Barr Virus (EBV) uses the gene EBER-1 to produce decoy dsRNA. This leads to cancers such as Burkitt's lymphoma, Hodgkin's Disease, nasopharyngeal carcinoma and various leukemias.

Memory and learning

PKR knockout mice or inhibition of PKR in mice enhances memory and learning.^[8]

Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome.^[9]

Interactions

Protein kinase R has been shown to interact with:

• ASK1,^[10]
• DNAJC3,^[11][11]
• ILF3,^{[12][13][14][15]}
• METAP2,^[16]
• P53,^[17]
• PPP1CA,^[18]
• PRKRA,^[19][20]
• STAT1,^[21][22] and
• TARBP2.^[23][24]

References

Further reading

PDB gallery
1qu6: STRUCTURE OF THE DOUBLE-STRANDED RNA-BINDING DOMAIN OF THE PROTEIN KINASE PKR REVEALS THE MOLECULAR BASIS OF ITS DSRNA-MEDIATED ACTIVATION  2a19: PKR kinase domain- eIF2alpha- AMP-PNP complex.  2a1a: PKR kinase domain-eIF2alpha Complex