Protein kinase R

Protein kinase R

Protein kinase R (Eukaryotic translation initiation factor 2-alpha kinase 2) is a protein protecting against viral infections. EIF2AK2 is its human gene.cite web | title = Entrez Gene: EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&list_uids=5610&rn=1| accessdate = ]

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 defense

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.

References

Further reading

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

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