Protein kinase R Information & Protein kinase R Links at HealthHaven.com

Eukaryotic translation initiation factor 2-alpha kinase 2
	; NMR structure of the double stranded RNA binding domain of EIF2AK2 based on PDB 1qu6.
Available structures
	1qu6, 2a19, 2a1a
Identifiers
Symbols	EIF2AK2; EIF2AK1; MGC126524; PKR; PRKR
External IDs	OMIM: 176871 MGI: 1353449 HomoloGene: 48134 GeneCards: EIF2AK2 Gene
Gene ontology
Molecular function	• nucleotide binding; • double-stranded RNA binding; • protein kinase activity; • protein serine/threonine kinase activity; • eukaryotic translation initiation factor 2alpha kinase activity; • protein binding; • ATP binding; • protein phosphatase type 2A regulator activity; • transferase activity;
Cellular component	• intracellular;
Biological process	• regulation of transcription, DNA-dependent; • translation; • protein amino acid phosphorylation; • virus-infected cell apoptosis; • immune response; • cell cycle; • negative regulation of cell proliferation; • response to virus; • unfolded protein response; • protein amino acid autophosphorylation;
RNA expression pattern
	More reference expression data
Orthologs

edit

Protein kinase R or PKR (Eukaryotic translation initiation factor 2-alpha kinase 2) is a protein protecting against viral infections. EIF2AK2 is its human gene.^[1]

[edit] Mechanism

PKR is activated by double-stranded RNA (dsRNA), the synthesis of which is caused virally. 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.

[edit] 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.

[edit] Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome.[www.lifescience.net.cn/download.asp?ID=649]

Viral defence mechanisms against PKR
Defence type	Virus	Molecule
Decoy dsRNA	Adenovirus	VA RNA
	Epstein-Barr virus	EBER
	HIV	TAR
PKR degradation	Poliovirus	2A^pro
hide viral dsRNA	vaccinia virus	E3L
	Reovirus	σ3
	Influenza virus	NS1
Dimerization block	Influenza virus	p58^IPK
Dimerization block	hepatitis C virus	NS5A
Pseudosubstrate	Vaccinia virus	K3L
Pseudosubstrate	HIV	Tat
dephosphorylation of substrate	herpes simplex virus	ICP34.5

[edit] Interactions

Protein kinase R has been shown to interact with ASK1,^[2] PPP1CA,^[3] STAT1,^[4]^[5] ILF3,^[6]^[7]^[8]^[9] DNAJC3,^[10]^[11] P53,^[12] TARBP2,^[13]^[14] METAP2^[15] and PRKRA.^[16]^[17]

[edit] References

^ "Entrez Gene: EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2". http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&list_uids=5610&rn=1.
^ Takizawa, Takenori; Tatematsu Chizuru, Nakanishi Yoshinobu (Dec. 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". Eur. J. Biochem. (Germany) 269 (24): 6126–32. ISSN 0014-2956. PMID 12473108.
^ Tan, Seng-Lai; Tareen Semih U, Melville Mark W, Blakely Collin M, Katze Michael G (Sep. 2002). "The direct binding of the catalytic subunit of protein phosphatase 1 to the PKR protein kinase is necessary but not sufficient for inactivation and disruption of enzyme dimer formation". J. Biol. Chem. (United States) 277 (39): 36109–17. doi:10.1074/jbc.M205109200. ISSN 0021-9258. PMID 12138106.
^ Wong, A H; Tam N W, Yang Y L, Cuddihy A R, Li S, Kirchhoff S, Hauser H, Decker T, Koromilas A E (Mar. 1997). "Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways". EMBO J. (ENGLAND) 16 (6): 1291–304. doi:10.1093/emboj/16.6.1291. ISSN 0261-4189. PMID 9135145.
^ Wong, A H; Durbin J E, Li S, Dever T E, Decker T, Koromilas A E (Apr. 2001). "Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR". J. Biol. Chem. (United States) 276 (17): 13727–37. doi:10.1074/jbc.M011240200. ISSN 0021-9258. PMID 11278865.
^ Saunders, L R; Perkins D J, Balachandran S, Michaels R, Ford R, Mayeda A, Barber G N (Aug. 2001). "Characterization of two evolutionarily conserved, alternatively spliced nuclear phosphoproteins, NFAR-1 and -2, that function in mRNA processing and interact with the double-stranded RNA-dependent protein kinase, PKR". J. Biol. Chem. (United States) 276 (34): 32300–12. doi:10.1074/jbc.M104207200. ISSN 0021-9258. PMID 11438536.
^ Langland, J O; Kao P N, Jacobs B L (May. 1999). "Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR". Biochemistry (UNITED STATES) 38 (19): 6361–8. doi:10.1021/bi982410u. ISSN 0006-2960. PMID 10320367.
^ Parker, L M; Fierro-Monti I, Mathews M B (Aug. 2001). "Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase". J. Biol. Chem. (United States) 276 (35): 32522–30. doi:10.1074/jbc.M104408200. ISSN 0021-9258. PMID 11438540.
^ Patel, R C; Vestal D J, Xu Z, Bandyopadhyay S, Guo W, Erme S M, Williams B R, Sen G C (Jul. 1999). "DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR". J. Biol. Chem. (UNITED STATES) 274 (29): 20432–7. ISSN 0021-9258. PMID 10400669.
^ Polyak, S J; Tang N, Wambach M, Barber G N, Katze M G (Jan. 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. (UNITED STATES) 271 (3): 1702–7. ISSN 0021-9258. PMID 8576172.
^ Gale, M; Blakely C M, Hopkins D A, Melville M W, Wambach M, Romano P R, Katze M G (Feb. 1998). "Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK". Mol. Cell. Biol. (UNITED STATES) 18 (2): 859–71. ISSN 0270-7306. PMID 9447982.
^ Cuddihy, A R; Wong A H, Tam N W, Li S, Koromilas A E (Apr. 1999). "The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro". Oncogene (ENGLAND) 18 (17): 2690–702. doi:10.1038/sj.onc.1202620. ISSN 0950-9232. PMID 10348343.
^ Cosentino, G P; Venkatesan S, Serluca F C, Green S R, Mathews M B, Sonenberg N (Oct. 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. (UNITED STATES) 92 (21): 9445–9. ISSN 0027-8424. PMID 7568151.
^ Daher, A; Longuet M, Dorin D, Bois F, Segeral E, Bannwarth S, Battisti P L, Purcell D F, Benarous R, Vaquero C, Meurs E F, Gatignol A (Sep. 2001). "Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression". J. Biol. Chem. (United States) 276 (36): 33899–905. doi:10.1074/jbc.M103584200. ISSN 0021-9258. PMID 11438532.
^ Gil, J; Esteban M, Roth D (Dec. 2000). "In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67". Biochemistry (UNITED STATES) 39 (51): 16016–25. ISSN 0006-2960. PMID 11123929.
^ Huang, Xu; Hutchins Brian, Patel Rekha C (Aug. 2002). "The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR)". Biochem. J. (England) 366 (Pt 1): 175–86. doi:10.1042/BJ20020204. ISSN 0264-6021. PMID 11985496.
^ Patel, R C; Sen G C (Aug. 1998). "PACT, a protein activator of the interferon-induced protein kinase, PKR". EMBO J. (ENGLAND) 17 (15): 4379–90. doi:10.1093/emboj/17.15.4379. ISSN 0261-4189. PMID 9687506.

[edit] 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.
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. doi:10.1073/pnas.89.12.5447. PMID 1351683.
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. doi:10.1016/0042-6822(92)90732-5. PMID 1373553.
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. doi:10.1016/0042-6822(92)90733-6. PMID 1373554.
Mellor H, Proud CG (1991). "A synthetic peptide substrate for initiation factor-2 kinases.". Biochem. Biophys. Res. Commun. 178 (2): 430–7. doi:10.1016/0006-291X(91)90125-Q. 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. doi:10.1016/0092-8674(90)90374-N. PMID 1695551.
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. doi:10.1126/science.2180064. PMID 2180064.
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.
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. doi:10.1073/pnas.92.21.9445. PMID 7568151.
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.
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.
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. doi:10.1074/jbc.270.18.10717. PMID 7738010.
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. doi:10.1073/pnas.90.10.4621. PMID 8099444.
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. doi:10.1074/jbc.271.3.1702. PMID 8576172.
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. doi:10.1016/S0092-8674(00)81064-8. PMID 8601309.
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.
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.
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. doi:10.1016/0378-1119(96)00314-9. PMID 8921913.

This transferase article is a stub. You can help Wikipedia by expanding it.

[entrez-0] "Entrez Gene: EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2". http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&list_uids=5610&rn=1.

[pmid12473108-1] Takizawa, Takenori; Tatematsu Chizuru, Nakanishi Yoshinobu (Dec. 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". Eur. J. Biochem. (Germany) 269 (24): 6126–32. ISSN 0014-2956. PMID 12473108.

[pmid12138106-2] Tan, Seng-Lai; Tareen Semih U, Melville Mark W, Blakely Collin M, Katze Michael G (Sep. 2002). "The direct binding of the catalytic subunit of protein phosphatase 1 to the PKR protein kinase is necessary but not sufficient for inactivation and disruption of enzyme dimer formation". J. Biol. Chem. (United States) 277 (39): 36109–17. doi:10.1074/jbc.M205109200. ISSN 0021-9258. PMID 12138106.

[pmid9135145-3] Wong, A H; Tam N W, Yang Y L, Cuddihy A R, Li S, Kirchhoff S, Hauser H, Decker T, Koromilas A E (Mar. 1997). "Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways". EMBO J. (ENGLAND) 16 (6): 1291–304. doi:10.1093/emboj/16.6.1291. ISSN 0261-4189. PMID 9135145.

[pmid11278865-4] Wong, A H; Durbin J E, Li S, Dever T E, Decker T, Koromilas A E (Apr. 2001). "Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR". J. Biol. Chem. (United States) 276 (17): 13727–37. doi:10.1074/jbc.M011240200. ISSN 0021-9258. PMID 11278865.

[pmid11438536-5] Saunders, L R; Perkins D J, Balachandran S, Michaels R, Ford R, Mayeda A, Barber G N (Aug. 2001). "Characterization of two evolutionarily conserved, alternatively spliced nuclear phosphoproteins, NFAR-1 and -2, that function in mRNA processing and interact with the double-stranded RNA-dependent protein kinase, PKR". J. Biol. Chem. (United States) 276 (34): 32300–12. doi:10.1074/jbc.M104207200. ISSN 0021-9258. PMID 11438536.

[pmid10320367-6] Langland, J O; Kao P N, Jacobs B L (May. 1999). "Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR". Biochemistry (UNITED STATES) 38 (19): 6361–8. doi:10.1021/bi982410u. ISSN 0006-2960. PMID 10320367.

[pmid11438540-7] Parker, L M; Fierro-Monti I, Mathews M B (Aug. 2001). "Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase". J. Biol. Chem. (United States) 276 (35): 32522–30. doi:10.1074/jbc.M104408200. ISSN 0021-9258. PMID 11438540.

[pmid10400669-8] Patel, R C; Vestal D J, Xu Z, Bandyopadhyay S, Guo W, Erme S M, Williams B R, Sen G C (Jul. 1999). "DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR". J. Biol. Chem. (UNITED STATES) 274 (29): 20432–7. ISSN 0021-9258. PMID 10400669.

[pmid8576172-9] Polyak, S J; Tang N, Wambach M, Barber G N, Katze M G (Jan. 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. (UNITED STATES) 271 (3): 1702–7. ISSN 0021-9258. PMID 8576172.

[pmid9447982-10] Gale, M; Blakely C M, Hopkins D A, Melville M W, Wambach M, Romano P R, Katze M G (Feb. 1998). "Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK". Mol. Cell. Biol. (UNITED STATES) 18 (2): 859–71. ISSN 0270-7306. PMID 9447982.

[pmid10348343-11] Cuddihy, A R; Wong A H, Tam N W, Li S, Koromilas A E (Apr. 1999). "The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro". Oncogene (ENGLAND) 18 (17): 2690–702. doi:10.1038/sj.onc.1202620. ISSN 0950-9232. PMID 10348343.

[pmid7568151-12] Cosentino, G P; Venkatesan S, Serluca F C, Green S R, Mathews M B, Sonenberg N (Oct. 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. (UNITED STATES) 92 (21): 9445–9. ISSN 0027-8424. PMID 7568151.

[pmid11438532-13] Daher, A; Longuet M, Dorin D, Bois F, Segeral E, Bannwarth S, Battisti P L, Purcell D F, Benarous R, Vaquero C, Meurs E F, Gatignol A (Sep. 2001). "Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression". J. Biol. Chem. (United States) 276 (36): 33899–905. doi:10.1074/jbc.M103584200. ISSN 0021-9258. PMID 11438532.

[pmid11123929-14] Gil, J; Esteban M, Roth D (Dec. 2000). "In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67". Biochemistry (UNITED STATES) 39 (51): 16016–25. ISSN 0006-2960. PMID 11123929.

[pmid11985496-15] Huang, Xu; Hutchins Brian, Patel Rekha C (Aug. 2002). "The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR)". Biochem. J. (England) 366 (Pt 1): 175–86. doi:10.1042/BJ20020204. ISSN 0264-6021. PMID 11985496.

[pmid9687506-16] Patel, R C; Sen G C (Aug. 1998). "PACT, a protein activator of the interferon-induced protein kinase, PKR". EMBO J. (ENGLAND) 17 (15): 4379–90. doi:10.1093/emboj/17.15.4379. ISSN 0261-4189. PMID 9687506.

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