Protein kinase R

Eukaryotic translation initiation factor 2-alpha kinase 2
File:PBB Protein EIF2AK2 image.jpg PDB rendering based on 1qu6.
Available structures PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB List of PDB id codes 1qu6​, 2a19​, 2a1a​
Identifiers
Symbols	EIF2AK2 ; EIF2AK1; MGC126524; PKR; PRKR
External IDs	Template:OMIM5 Template:MGI HomoloGene: 48134
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Cellular component Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
File:PBB GE EIF2AK2 204211 x at tn.png
File:PBB GE EIF2AK2 213294 at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

Protein kinase R (Eukaryotic translation initiation factor 2-alpha kinase 2) is a protein protecting against viral infections. EIF2AK2 is its human gene.

Mechanism

PKR is activated by double-stranded RNA (dsRNA), produced by virus. 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 autophosphorylation reactions. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein and causing apoptosis of the cell to prevent further viral spread.

Viral defence

Viruses have developed many mechanisms to outfox 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.

Viral defence mechanisms against PKR

Defence type	Virus	Molecule
Decoy dsRNA	Adenovirus	VA RNA
	Epstein-Barr virus	EBER
	HIV	TAR
PKR degradation	Poliovirus	2Apro
hide viral dsRNA	vaccinia virus	E3L
	Reovirus	σ3
	Influenza virus	NS1
Dimerization block	Influenza virus	p58IPK
	hepatitis C virus	NS5A
Pseudosubstrate	Vaccinia virus	K3L
	HIV	Tat
dephosphorylation of substrate	herpes simplex virus	γ134.5

Further reading

• Williams BR (1999). "PKR; a sentinel kinase for cellular stress". Oncogene. 18 (45): 6112–20. doi:10.1038/sj.onc.1203127. PMID 10557102.
• García MA, Meurs EF, Esteban M (2007). "The dsRNA protein kinase PKR: virus and cell control". Biochimie. 89 (6–7): 799–811. doi:10.1016/j.biochi.2007.03.001. PMID 17451862.CS1 maint: Multiple names: authors list (link)
• Feng GS, Chong K, Kumar A, Williams BR (1992). "Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase". Proc. Natl. Acad. Sci. U.S.A. 89 (12): 5447–51. PMID 1351683.CS1 maint: Multiple names: authors list (link)
• Thomis DC, Doohan JP, Samuel CE (1992). "Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells". Virology. 188 (1): 33–46. PMID 1373553.CS1 maint: Multiple names: authors list (link)
• McCormack SJ, Thomis DC, Samuel CE (1992). "Mechanism of interferon action: identification of a RNA binding domain within the N-terminal region of the human RNA-dependent P1/eIF-2 alpha protein kinase". Virology. 188 (1): 47–56. PMID 1373554.CS1 maint: Multiple names: authors list (link)
• Mellor H, Proud CG (1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochem. Biophys. Res. Commun. 178 (2): 430–7. PMID 1677563.
• Meurs E, Chong K, Galabru J; et al. (1990). "Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon". Cell. 62 (2): 379–90. PMID 1695551.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Silverman RH, Sengupta DN (1991). "Translational regulation by HIV leader RNA, TAT, and interferon-inducible enzymes". J. Exp. Pathol. 5 (2): 69–77. PMID 1708818.
• Roy S, Katze MG, Parkin NT; et al. (1990). "Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product". Science. 247 (4947): 1216–9. PMID 2180064.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• McMillan NA, Chun RF, Siderovski DP; et al. (1996). "HIV-1 Tat directly interacts with the interferon-induced, double-stranded RNA-dependent kinase, PKR". Virology. 213 (2): 413–24. doi:10.1006/viro.1995.0014. PMID 7491766.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Cosentino GP, Venkatesan S, Serluca FC; et al. (1995). "Double-stranded-RNA-dependent protein kinase and TAR RNA-binding protein form homo- and heterodimers in vivo". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9445–9. PMID 7568151.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Barber GN, Edelhoff S, Katze MG, Disteche CM (1993). "Chromosomal assignment of the interferon-inducible double-stranded RNA-dependent protein kinase (PRKR) to human chromosome 2p21-p22 and mouse chromosome 17 E2". Genomics. 16 (3): 765–7. doi:10.1006/geno.1993.1262. PMID 7686883.CS1 maint: Multiple names: authors list (link)
• Squire J, Meurs EF, Chong KL; et al. (1993). "Localization of the human interferon-induced, ds-RNA activated p68 kinase gene (PRKR) to chromosome 2p21-p22". Genomics. 16 (3): 768–70. doi:10.1006/geno.1993.1263. PMID 7686884.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Prigmore E, Ahmed S, Best A; et al. (1995). "A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils". J. Biol. Chem. 270 (18): 10717–22. PMID 7738010.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Barber GN, Wambach M, Wong ML; et al. (1993). "Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase". Proc. Natl. Acad. Sci. U.S.A. 90 (10): 4621–5. PMID 8099444.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Polyak SJ, Tang N, Wambach M; et al. (1996). "The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity". J. Biol. Chem. 271 (3): 1702–7. PMID 8576172.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Chen ZJ, Parent L, Maniatis T (1996). "Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity". Cell. 84 (6): 853–62. PMID 8601309.CS1 maint: Multiple names: authors list (link)
• Kuhen KL, Shen X, Carlisle ER; et al. (1997). "Structural organization of the human gene (PKR) encoding an interferon-inducible RNA-dependent protein kinase (PKR) and differences from its mouse homolog". Genomics. 36 (1): 197–201. doi:10.1006/geno.1996.0446. PMID 8812437.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Taylor DR, Lee SB, Romano PR; et al. (1996). "Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR". Mol. Cell. Biol. 16 (11): 6295–302. PMID 8887659.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Kuhen KL, Shen X, Samuel CE (1996). "Mechanism of interferon action sequence of the human interferon-inducible RNA-dependent protein kinase (PKR) deduced from genomic clones". Gene. 178 (1–2): 191–3. PMID 8921913.CS1 maint: Multiple names: authors list (link)