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Interferon-induced, double-stranded RNA-activated protein kinase (EC 2.7.11.1) (Eukaryotic translation initiation factor 2-alpha kinase 2) (eIF-2A protein kinase 2) (Interferon-inducible RNA-dependent protein kinase) (P1/eIF-2A protein kinase) (Protein kinase RNA-activated) (PKR) (Protein kinase R) (Tyrosine-protein kinase EIF2AK2) (EC 2.7.10.2) (p68 kinase)

 E2AK2_HUMAN             Reviewed;         551 AA.
P19525; A8K3P0; D6W584; E9PC80; Q52M43; Q7Z6F6; Q9UIR4;
01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
01-MAY-1991, sequence version 2.
31-JUL-2019, entry version 226.
RecName: Full=Interferon-induced, double-stranded RNA-activated protein kinase;
EC=2.7.11.1;
AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 2;
Short=eIF-2A protein kinase 2;
AltName: Full=Interferon-inducible RNA-dependent protein kinase;
AltName: Full=P1/eIF-2A protein kinase;
AltName: Full=Protein kinase RNA-activated;
Short=PKR;
Short=Protein kinase R {ECO:0000303|PubMed:11438532};
AltName: Full=Tyrosine-protein kinase EIF2AK2;
EC=2.7.10.2;
AltName: Full=p68 kinase;
Name=EIF2AK2; Synonyms=PKR, PRKR;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 101-118
AND 309-325, AND INDUCTION.
PubMed=1695551; DOI=10.1016/0092-8674(90)90374-N;
Meurs E., Chong K., Galabru J., Thomas N.S.B., Kerr I.M.,
Williams B.R.G., Hovanessian A.G.;
"Molecular cloning and characterization of the human double-stranded
RNA-activated protein kinase induced by interferon.";
Cell 62:379-390(1990).
[2]
SEQUENCE REVISION.
Meurs E.;
Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=1373553; DOI=10.1016/0042-6822(92)90732-5;
Thomis D.C., Doohan J.P., Samuel C.E.;
"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 188:33-46(1992).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
PubMed=8921913; DOI=10.1016/0378-1119(96)00314-9;
Kuhen K.L., Shen X., Samuel C.E.;
"Mechanism of interferon action sequence of the human interferon-
inducible RNA-dependent protein kinase (PKR) deduced from genomic
clones.";
Gene 178:191-193(1996).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
TISSUE=Placenta;
PubMed=8812437; DOI=10.1006/geno.1996.0446;
Kuhen K.L., Shen X., Carlisle E.R., Richardson A.L., Weier H.-U.G.,
Tanaka H., Samuel C.E.;
"Structural organization of the human gene (PKR) encoding an
interferon-inducible RNA-dependent protein kinase (PKR) and
differences from its mouse homolog.";
Genomics 36:197-201(1996).
[6]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=9726442; DOI=10.1089/jir.1998.18.609;
Xu Z., Williams B.R.;
"Genomic features of human PKR: alternative splicing and a polymorphic
CGG repeat in the 5'-untranslated region.";
J. Interferon Cytokine Res. 18:609-616(1998).
[7]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
Li H., Huang F., Shen C., Zhou G., Zheng G., Ke R., Lin L., Yang S.;
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Brain, and Embryo;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[9]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
NIEHS SNPs program;
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[11]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[12]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Brain;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[13]
PROTEIN SEQUENCE OF 2-18; 27-40; 70-77; 414-426 AND 430-440, CLEAVAGE
OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY
MASS SPECTROMETRY.
TISSUE=Prostatic carcinoma;
Bienvenut W.V., Gao M., Leug H.;
Submitted (JUN-2009) to UniProtKB.
[14]
INTERACTION WITH DNAJC3.
PubMed=8576172; DOI=10.1074/jbc.271.3.1702;
Polyak S.J., Tang N., Wambach M., Barber G.N., Katze M.G.;
"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. 271:1702-1707(1996).
[15]
INTERACTION WITH HIV-1 TAT.
PubMed=9079663; DOI=10.1074/jbc.272.13.8388;
Brand S.R., Kobayashi R., Mathews M.B.;
"The Tat protein of human immunodeficiency virus type 1 is a substrate
and inhibitor of the interferon-induced, virally activated protein
kinase, PKR.";
J. Biol. Chem. 272:8388-8395(1997).
[16]
INTERACTION WITH HCV NS5A.
PubMed=9143277; DOI=10.1006/viro.1997.8493;
Gale M.J. Jr., Korth M.J., Tang N.M., Tan S.-L., Hopkins D.A.,
Dever T.E., Polyak S.J., Gretch D.R., Katze M.G.;
"Evidence that hepatitis C virus resistance to interferon is mediated
through repression of the PKR protein kinase by the nonstructural 5A
protein.";
Virology 230:217-227(1997).
[17]
INTERACTION WITH INFLUENZA A NS1 PROTEIN.
PubMed=9781815; DOI=10.1089/jir.1998.18.757;
Tan S.L., Katze M.G.;
"Biochemical and genetic evidence for complex formation between the
influenza A virus NS1 protein and the interferon-induced PKR protein
kinase.";
J. Interferon Cytokine Res. 18:757-766(1998).
[18]
INTERACTION WITH HCV E2 ENVELOPE PROTEIN.
PubMed=10390359; DOI=10.1126/science.285.5424.107;
Taylor D.R., Shi S.T., Romano P.R., Barber G.N., Lai M.M.C.;
"Inhibition of the interferon-inducible protein kinase PKR by HCV E2
protein.";
Science 285:107-110(1999).
[19]
FUNCTION, AND INTERACTION WITH IKBKB.
PubMed=10848580; DOI=10.1128/MCB.20.13.4532-4542.2000;
Bonnet M.C., Weil R., Dam E., Hovanessian A.G., Meurs E.F.;
"PKR stimulates NF-kappaB irrespective of its kinase function by
interacting with the IkappaB kinase complex.";
Mol. Cell. Biol. 20:4532-4542(2000).
[20]
INTERACTION WITH TARBP2.
PubMed=11438532; DOI=10.1074/jbc.M103584200;
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.;
"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. 276:33899-33905(2001).
[21]
PHOSPHORYLATION AT SER-83; THR-88; THR-89; THR-90; SER-242; THR-255
AND THR-258, MUTAGENESIS OF SER-83; THR-88; THR-89; THR-90; SER-242;
THR-255; THR-258 AND LYS-296, AND INHIBITION BY HCV E2 ENVELOPE
PROTEIN.
PubMed=11152499; DOI=10.1128/JVI.75.3.1265-1273.2001;
Taylor D.R., Tian B., Romano P.R., Hinnebusch A.G., Lai M.M.C.,
Mathews M.B.;
"Hepatitis C virus envelope protein E2 does not inhibit PKR by simple
competition with autophosphorylation sites in the RNA-binding
domain.";
J. Virol. 75:1265-1273(2001).
[22]
MUTAGENESIS, AND PHOSPHORYLATION AT THR-446 AND THR-451.
PubMed=11337501; DOI=10.1074/jbc.M102108200;
Zhang F., Romano P.R., Nagamura-Inoue T., Tian B., Dever T.E.,
Mathews M.B., Ozato K., Hinnebusch A.G.;
"Binding of double-stranded RNA to protein kinase PKR is required for
dimerization and promotes critical autophosphorylation events in the
activation loop.";
J. Biol. Chem. 276:24946-24958(2001).
[23]
INTERACTION WITH HHV-8 PROTEIN VIRF2 (MICROBIAL INFECTION).
PubMed=11160738; DOI=10.1128/JVI.75.5.2345-2352.2001;
Burysek L., Pitha P.M.;
"Latently expressed human herpesvirus 8-encoded interferon regulatory
factor 2 inhibits double-stranded RNA-activated protein kinase.";
J. Virol. 75:2345-2352(2001).
[24]
FUNCTION, AND INTERACTION WITH HHV-1 US11 (MICROBIAL INFECTION).
PubMed=11836380; DOI=10.1128/jvi.76.5.2029-2035.2002;
Cassady K.A., Gross M.;
"The herpes simplex virus type 1 U(S)11 protein interacts with protein
kinase R in infected cells and requires a 30-amino-acid sequence
adjacent to a kinase substrate domain.";
J. Virol. 76:2029-2035(2002).
[25]
INTERACTION WITH NPM1, AND ACTIVITY REGULATION.
PubMed=12882984; DOI=10.1074/jbc.M301392200;
Pang Q., Christianson T.A., Koretsky T., Carlson H., David L.,
Keeble W., Faulkner G.R., Speckhart A., Bagby G.C.;
"Nucleophosmin interacts with and inhibits the catalytic function of
eukaryotic initiation factor 2 kinase PKR.";
J. Biol. Chem. 278:41709-41717(2003).
[26]
FUNCTION, AND INTERACTION WITH MAP2K6.
PubMed=15229216; DOI=10.1074/jbc.M406554200;
Silva A.M., Whitmore M., Xu Z., Jiang Z., Li X., Williams B.R.;
"Protein kinase R (PKR) interacts with and activates mitogen-activated
protein kinase kinase 6 (MKK6) in response to double-stranded RNA
stimulation.";
J. Biol. Chem. 279:37670-37676(2004).
[27]
IDENTIFICATION IN A COMPLEX WITH FANCA; FANCC; FANCG AND HSP70.
PubMed=15299030; DOI=10.1074/jbc.M403884200;
Zhang X., Li J., Sejas D.P., Rathbun K.R., Bagby G.C., Pang Q.;
"The Fanconi anemia proteins functionally interact with the protein
kinase regulated by RNA (PKR).";
J. Biol. Chem. 279:43910-43919(2004).
[28]
FUNCTION, INTERACTION WITH TRAF2; TRAF5 AND TRAF6, AND SUBCELLULAR
LOCATION.
PubMed=15121867; DOI=10.1128/MCB.24.10.4502-4512.2004;
Gil J., Garcia M.A., Gomez-Puertas P., Guerra S., Rullas J.,
Nakano H., Alcami J., Esteban M.;
"TRAF family proteins link PKR with NF-kappa B activation.";
Mol. Cell. Biol. 24:4502-4512(2004).
[29]
INHIBITION BY VACCINIA VIRUS PROTEIN E3.
PubMed=15207627; DOI=10.1016/j.virol.2004.03.012;
Langland J.O., Jacobs B.L.;
"Inhibition of PKR by vaccinia virus: role of the N- and C-terminal
domains of E3L.";
Virology 324:419-429(2004).
[30]
REVIEW.
PubMed=17158706; DOI=10.1128/MMBR.00027-06;
Garcia M.A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C.,
Esteban M.;
"Impact of protein kinase PKR in cell biology: from antiviral to
antiproliferative action.";
Microbiol. Mol. Biol. Rev. 70:1032-1060(2006).
[31]
PHOSPHORYLATION AT TYR-101; TYR-162 AND TYR-293.
PubMed=16373505; DOI=10.1073/pnas.0508207103;
Su Q., Wang S., Baltzis D., Qu L.K., Wong A.H., Koromilas A.E.;
"Tyrosine phosphorylation acts as a molecular switch to full-scale
activation of the eIF2alpha RNA-dependent protein kinase.";
Proc. Natl. Acad. Sci. U.S.A. 103:63-68(2006).
[32]
INTERACTION WITH ADAR.
PubMed=17079286; DOI=10.1128/JVI.01527-06;
Nie Y., Hammond G.L., Yang J.H.;
"Double-stranded RNA deaminase ADAR1 increases host susceptibility to
virus infection.";
J. Virol. 81:917-923(2007).
[33]
REVIEW ON ACTIVITY REGULATION.
PubMed=17196820; DOI=10.1016/j.tibs.2006.12.003;
Cole J.L.;
"Activation of PKR: an open and shut case?";
Trends Biochem. Sci. 32:57-62(2007).
[34]
FUNCTION, INTERACTION WITH NCK1, AND ACTIVITY REGULATION.
PubMed=18835251; DOI=10.1016/j.bbrc.2008.09.112;
Cardin E., Larose L.;
"Nck-1 interacts with PKR and modulates its activation by dsRNA.";
Biochem. Biophys. Res. Commun. 377:231-235(2008).
[35]
INTERACTION WITH DUS2L, AND ACTIVITY REGULATION.
PubMed=18096616; DOI=10.1093/nar/gkm1129;
Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V.,
Patel R.C.;
"Interaction of human tRNA-dihydrouridine synthase-2 with interferon-
induced protein kinase PKR.";
Nucleic Acids Res. 36:998-1008(2008).
[36]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83 AND SER-456, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[37]
FUNCTION.
PubMed=19507191; DOI=10.1002/jcp.21848;
Blalock W.L., Grimaldi C., Fala F., Follo M., Horn S., Basecke J.,
Martinelli G., Cocco L., Martelli A.M.;
"PKR activity is required for acute leukemic cell maintenance and
growth: a role for PKR-mediated phosphatase activity to regulate GSK-3
phosphorylation.";
J. Cell. Physiol. 221:232-241(2009).
[38]
FUNCTION, AND INTERACTION WITH DHX9.
PubMed=19229320; DOI=10.1371/journal.ppat.1000311;
Sadler A.J., Latchoumanin O., Hawkes D., Mak J., Williams B.R.;
"An antiviral response directed by PKR phosphorylation of the RNA
helicase A.";
PLoS Pathog. 5:E1000311-E1000311(2009).
[39]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[40]
FUNCTION IN HCV RESTRICTION.
PubMed=19189853; DOI=10.1016/j.virusres.2009.01.007;
Kang J.I., Kwon S.N., Park S.H., Kim Y.K., Choi S.Y., Kim J.P.,
Ahn B.Y.;
"PKR protein kinase is activated by hepatitis C virus and inhibits
viral replication through translational control.";
Virus Res. 142:51-56(2009).
[41]
FUNCTION.
PubMed=20171114; DOI=10.1016/j.cyto.2010.01.008;
Lin S.S., Lee D.C., Law A.H., Fang J.W., Chua D.T., Lau A.S.;
"A role for protein kinase PKR in the mediation of Epstein-Barr virus
latent membrane protein-1-induced IL-6 and IL-10 expression.";
Cytokine 50:210-219(2010).
[42]
FUNCTION AS CDK1 KINASE UPON DNA DAMAGE, AND FUNCTION AS
TYROSINE-PROTEIN KINASE.
PubMed=20395957; DOI=10.1038/embor.2010.45;
Yoon C.-H., Miah M.A., Kim K.P., Bae Y.-S.;
"New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase
triggers Cdc2 polyubiquitination and G2 arrest under genotoxic
stresses.";
EMBO Rep. 11:393-399(2010).
[43]
FUNCTION.
PubMed=21123651; DOI=10.1101/gad.1965010;
Harashima A., Guettouche T., Barber G.N.;
"Phosphorylation of the NFAR proteins by the dsRNA-dependent protein
kinase PKR constitutes a novel mechanism of translational regulation
and cellular defense.";
Genes Dev. 24:2640-2653(2010).
[44]
FUNCTION IN HCV RESTRICTION.
PubMed=19840259; DOI=10.1111/j.1478-3231.2009.02144.x;
Chang J.H., Kato N., Muroyama R., Taniguchi H., Guleng B., Dharel N.,
Shao R.X., Tateishi K., Jazag A., Kawabe T., Omata M.;
"Double-stranded RNA-activated protein kinase inhibits hepatitis C
virus replication but may be not essential in interferon treatment.";
Liver Int. 30:311-318(2010).
[45]
FUNCTION, AND PHOSPHORYLATION AT THR-451.
PubMed=20685959; DOI=10.1091/mbc.E10-06-0481;
Yang X., Nath A., Opperman M.J., Chan C.;
"The double-stranded RNA-dependent protein kinase differentially
regulates insulin receptor substrates 1 and 2 in HepG2 cells.";
Mol. Biol. Cell 21:3449-3458(2010).
[46]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=20068231; DOI=10.1126/scisignal.2000475;
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
Mann M.;
"Quantitative phosphoproteomics reveals widespread full
phosphorylation site occupancy during mitosis.";
Sci. Signal. 3:RA3-RA3(2010).
[47]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[48]
SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x;
Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F.,
Hugon J.;
"Modulation of tau phosphorylation by the kinase PKR: implications in
Alzheimer's disease.";
Brain Pathol. 21:189-200(2011).
[49]
REVIEW.
PubMed=21924887; DOI=10.1016/j.coi.2011.08.009;
Pfaller C.K., Li Z., George C.X., Samuel C.E.;
"Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for
old players as modulators of the interferon response.";
Curr. Opin. Immunol. 23:573-582(2011).
[50]
REVIEW.
PubMed=21166592; DOI=10.1089/jir.2010.0099;
Pindel A., Sadler A.;
"The role of protein kinase R in the interferon response.";
J. Interferon Cytokine Res. 31:59-70(2011).
[51]
FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY,
AND PHOSPHORYLATION.
PubMed=21072047; DOI=10.1038/leu.2010.264;
Blalock W.L., Bavelloni A., Piazzi M., Tagliavini F., Faenza I.,
Martelli A.M., Follo M.Y., Cocco L.;
"Multiple forms of PKR present in the nuclei of acute leukemia cells
represent an active kinase that is responsive to stress.";
Leukemia 25:236-245(2011).
[52]
FUNCTION IN HBV RESTRICTION.
PubMed=21710204; DOI=10.1007/s10059-011-1059-6;
Park I.H., Baek K.W., Cho E.Y., Ahn B.Y.;
"PKR-dependent mechanisms of interferon-? for inhibiting hepatitis B
virus replication.";
Mol. Cells 32:167-172(2011).
[53]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=22214662; DOI=10.4161/cc.11.2.18999;
Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.;
"The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and
activation, leading to G(1) arrest.";
Cell Cycle 11:407-417(2012).
[54]
REVIEW.
PubMed=22633454; DOI=10.1016/j.immuni.2012.05.010;
Lacy-Hulbert A., Stuart L.M.;
"Penetration resistance: PKR's other talent.";
Immunity 36:695-696(2012).
[55]
FUNCTION.
PubMed=22948139; DOI=10.1074/jbc.M112.390039;
McAllister C.S., Taghavi N., Samuel C.E.;
"Protein kinase PKR amplification of interferon beta induction occurs
through initiation factor eIF-2alpha-mediated translational control.";
J. Biol. Chem. 287:36384-36392(2012).
[56]
FUNCTION, AND INTERACTION WITH STAT3.
PubMed=23084476; DOI=10.1016/j.molcel.2012.09.013;
Shen S., Niso-Santano M., Adjemian S., Takehara T., Malik S.A.,
Minoux H., Souquere S., Marino G., Lachkar S., Senovilla L.,
Galluzzi L., Kepp O., Pierron G., Maiuri M.C., Hikita H., Kroemer R.,
Kroemer G.;
"Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.";
Mol. Cell 48:667-680(2012).
[57]
ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22223895; DOI=10.1074/mcp.M111.015131;
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C.,
Meinnel T., Giglione C.;
"Comparative large-scale characterisation of plant vs. mammal proteins
reveals similar and idiosyncratic N-alpha acetylation features.";
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
[58]
FUNCTION, INTERACTION WITH NLRP1; NLRP3; NLRC4 AND AIM2, AND
AUTOPHOSPHORYLATION.
PubMed=22801494; DOI=10.1038/nature11290;
Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P.,
Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y.,
Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U.,
Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.;
"Novel role of PKR in inflammasome activation and HMGB1 release.";
Nature 488:670-674(2012).
[59]
ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22814378; DOI=10.1073/pnas.1210303109;
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
Aldabe R.;
"N-terminal acetylome analyses and functional insights of the N-
terminal acetyltransferase NatB.";
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
[60]
REVIEW.
PubMed=23092889; DOI=10.1126/scisignal.2003511;
Kang R., Tang D.;
"PKR-dependent inflammatory signals.";
Sci. Signal. 5:PE47-PE47(2012).
[61]
FUNCTION.
PubMed=22381929; DOI=10.1016/j.virol.2012.01.029;
Taghavi N., Samuel C.E.;
"Protein kinase PKR catalytic activity is required for the PKR-
dependent activation of mitogen-activated protein kinases and
amplification of interferon beta induction following virus
infection.";
Virology 427:208-216(2012).
[62]
REVIEW.
PubMed=23202496; DOI=10.3390/v4112598;
Dabo S., Meurs E.F.;
"dsRNA-dependent protein kinase PKR and its role in stress, signaling
and HCV infection.";
Viruses 4:2598-2635(2012).
[63]
TISSUE SPECIFICITY.
PubMed=23403623; DOI=10.1182/blood-2012-09-456400;
Liu X., Bennett R.L., Cheng X., Byrne M., Reinhard M.K., May W.S. Jr.;
"PKR regulates proliferation, differentiation and survival of murine
hematopoietic stem/progenitor cells.";
Blood 121:3364-3374(2013).
[64]
REVIEW.
PubMed=23354059; DOI=10.1007/s00018-012-1252-6;
Donnelly N., Gorman A.M., Gupta S., Samali A.;
"The eIF2alpha kinases: their structures and functions.";
Cell. Mol. Life Sci. 70:3493-3511(2013).
[65]
FUNCTION, ISGYLATION AT LYS-69 AND LYS-159, AND ACTIVITY REGULATION.
PubMed=23229543; DOI=10.1074/jbc.M112.401851;
Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E.,
Kamura T.;
"Activation of double-stranded RNA-activated protein kinase (PKR) by
interferon-stimulated gene 15 (ISG15) modification down-regulates
protein translation.";
J. Biol. Chem. 288:2839-2847(2013).
[66]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-542, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[67]
INTERACTION WITH TOSCANA VIRUS PROTEIN NSS (MICROBIAL INFECTION), AND
ACTIVITY REGULATION.
PubMed=23325696; DOI=10.1128/JVI.02506-12;
Kalveram B., Ikegami T.;
"Toscana virus NSs protein promoftes degradation of double-stranded
RNA-dependent protein kinase.";
J. Virol. 87:3710-3718(2013).
[68]
FUNCTION IN MV RESTRICTION.
PubMed=23115276; DOI=10.1128/JVI.02270-12;
Okonski K.M., Samuel C.E.;
"Stress granule formation induced by measles virus is protein kinase
PKR dependent and impaired by RNA adenosine deaminase ADAR1.";
J. Virol. 87:756-766(2013).
[69]
FUNCTION.
PubMed=23372823; DOI=10.1371/journal.pone.0055108;
Li Y., Xie J., Wu S., Xia J., Zhang P., Liu C., Zhang P., Huang X.;
"Protein kinase regulated by dsRNA downregulates the interferon
production in dengue virus- and dsrna-stimulated human lung epithelial
cells.";
PLoS ONE 8:E55108-E55108(2013).
[70]
FUNCTION IN HCV RESTRICTION.
PubMed=23399035; DOI=10.1016/j.virol.2013.01.015;
Zhang L., Alter H.J., Wang H., Jia S., Wang E., Marincola F.M.,
Shih J.W., Wang R.Y.;
"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 438:28-36(2013).
[71]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[72]
INTERACTION WITH VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION).
PubMed=25740987; DOI=10.1128/JVI.03288-14;
Dueck K.J., Hu Y.S., Chen P., Deschambault Y., Lee J., Varga J.,
Cao J.;
"Mutational analysis of vaccinia virus E3 protein: the biological
functions do not correlate with its biochemical capacity to bind
double-stranded RNA.";
J. Virol. 89:5382-5394(2015).
[73]
STRUCTURE BY NMR OF 1-175.
PubMed=9736623; DOI=10.1093/emboj/17.18.5458;
Nanduri S., Carpick B.W., Yang Y., Williams B.R.G., Qin J.;
"Structure of the double-stranded RNA-binding domain of the protein
kinase PKR reveals the molecular basis of its dsRNA-mediated
activation.";
EMBO J. 17:5458-5465(1998).
[74]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 258-550 IN COMPLEX WITH
EIF2ALPHA, AND PHOSPHORYLATION AT THR-446.
PubMed=16179258; DOI=10.1016/j.cell.2005.06.044;
Dar A.C., Dever T.E., Sicheri F.;
"Higher-order substrate recognition of eIF2alpha by the RNA-dependent
protein kinase PKR.";
Cell 122:887-900(2005).
[75]
VARIANTS [LARGE SCALE ANALYSIS] GLU-428; VAL-439 AND VAL-506.
PubMed=17344846; DOI=10.1038/nature05610;
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
-!- FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein
kinase which plays a key role in the innate immune response to
viral infection and is also involved in the regulation of signal
transduction, apoptosis, cell proliferation and differentiation.
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).
Inhibits viral replication via phosphorylation of the alpha
subunit of eukaryotic initiation factor 2 (EIF2S1), this
phosphorylation impairs the recycling of EIF2S1 between successive
rounds of initiation leading to inhibition of translation which
eventually results in shutdown of cellular and viral protein
synthesis. Also 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
proteosomal 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 proinflammatory 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. Can trigger apoptosis via FADD-mediated
activation of CASP8. Plays a role in the regulation of the
cytoskeleton by binding to gelsolin (GSN), sequestering the
protein in an inactive conformation away from actin.
{ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380,
ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216,
ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853,
ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191,
ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114,
ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959,
ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651,
ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662,
ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494,
ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476,
ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543,
ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035}.
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999,
ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216;
EC=2.7.11.1;
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
EC=2.7.11.1;
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-
tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136,
Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216;
EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};
-!- ACTIVITY REGULATION: Initially produced in an inactive form and is
activated by binding to viral dsRNA, which causes dimerization and
autophosphorylation in the activation loop and stimulation of
function. ISGylation can activate it in the absence of viral
infection. Can also be activated by heparin, proinflammatory
stimuli, growth factors, cytokines, oxidative stress and the
cellular protein PRKRA. Activity is markedly stimulated by
manganese ions. Activation is blocked by the viral components HIV-
1 Tat protein and large amounts of HIV-1 trans-activation response
(TAR) RNA element as well as by the cellular proteins TARBP2,
DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS)
and Rift valley fever virus (RVFV) NSS which promote its
proteasomal degradation. Inhibited by vaccinia virus protein E3,
probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984,
ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251,
ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}.
-!- SUBUNIT: Homodimer. Interacts with STRBP (By similarity).
Interacts with DNAJC3. Forms a complex with FANCA, FANCC, FANCG
and HSP70. Interacts with ADAR/ADAR1. Interacts with IRS1 (By
similarity). The inactive form interacts with NCK1 and GSN.
Interacts (via the kinase catalytic domain) with STAT3 (via SH2
domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-
terminus). Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1,
NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L
(via DRBM domain). Interacts with DHX9 (via N-terminus) and this
interaction is dependent upon activation of the kinase.
{ECO:0000250, ECO:0000269|PubMed:10390359,
ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11438532,
ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:15121867,
ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:15299030,
ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:17079286,
ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251,
ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:22801494,
ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:25740987,
ECO:0000269|PubMed:8576172, ECO:0000269|PubMed:9079663,
ECO:0000269|PubMed:9143277, ECO:0000269|PubMed:9781815}.
-!- SUBUNIT: (Microbial infection) Interacts with human herpes simplex
virus 1 (HHV-1) protein US11 in an RNA-dependent manner.
{ECO:0000269|PubMed:11836380}.
-!- SUBUNIT: (Microbial infection) The inactive form interacts with
Toscana virus (TOS) NSS. {ECO:0000269|PubMed:23325696}.
-!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8
protein v-IRF2; this interaction inhibits EIF2AK2 activation.
{ECO:0000269|PubMed:11160738}.
-!- SUBUNIT: (Microbial infection) Interacts with vaccinia protein E3.
{ECO:0000269|PubMed:25740987}.
-!- INTERACTION:
Self; NbExp=2; IntAct=EBI-640775, EBI-640775;
O92972:- (xeno); NbExp=2; IntAct=EBI-640775, EBI-6918883;
P27958:- (xeno); NbExp=4; IntAct=EBI-640775, EBI-6904269;
P06493:CDK1; NbExp=4; IntAct=EBI-640775, EBI-444308;
Q7L2E3:DHX30; NbExp=3; IntAct=EBI-640775, EBI-1211456;
Q96C10:DHX58; NbExp=2; IntAct=EBI-640775, EBI-744193;
Q08211:DHX9; NbExp=2; IntAct=EBI-640775, EBI-352022;
Q9UPY3:DICER1; NbExp=2; IntAct=EBI-640775, EBI-395506;
Q27968:DNAJC3 (xeno); NbExp=5; IntAct=EBI-640775, EBI-640793;
Q6P2E9:EDC4; NbExp=2; IntAct=EBI-640775, EBI-1006038;
P05198:EIF2S1; NbExp=5; IntAct=EBI-640775, EBI-1056162;
P56537:EIF6; NbExp=2; IntAct=EBI-640775, EBI-372243;
Q8IY81:FTSJ3; NbExp=2; IntAct=EBI-640775, EBI-744088;
P20639:K3L (xeno); NbExp=3; IntAct=EBI-640775, EBI-8674942;
Q9HCE1:MOV10; NbExp=2; IntAct=EBI-640775, EBI-1055820;
Q96P20:NLRP3; NbExp=6; IntAct=EBI-640775, EBI-6253230;
P06748:NPM1; NbExp=3; IntAct=EBI-640775, EBI-78579;
O75569:PRKRA; NbExp=4; IntAct=EBI-640775, EBI-713955;
O75569-1:PRKRA; NbExp=3; IntAct=EBI-640775, EBI-15588172;
Q9NUL3:STAU2; NbExp=2; IntAct=EBI-640775, EBI-722938;
Q15633:TARBP2; NbExp=2; IntAct=EBI-640775, EBI-978581;
Q9H0E2:TOLLIP; NbExp=2; IntAct=EBI-640775, EBI-74615;
P04487:US11 (xeno); NbExp=3; IntAct=EBI-640775, EBI-6150681;
Q2HR71:vIRF-2 (xeno); NbExp=2; IntAct=EBI-640775, EBI-8876177;
Q9UL40:ZNF346; NbExp=2; IntAct=EBI-640775, EBI-2462313;
-!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cytoplasm, perinuclear
region. Note=Nuclear localization is elevated in acute leukemia,
myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate
and lung cancer patient samples or cell lines as well as
neurocytes from advanced Creutzfeldt-Jakob disease patients.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=P19525-1; Sequence=Displayed;
Name=2;
IsoId=P19525-2; Sequence=VSP_046177;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Highly expressed in thymus, spleen and bone
marrow compared to non-hematopoietic tissues such as small
intestine, liver, or kidney tissues. Colocalizes with GSK3B and
TAU in the Alzheimer disease (AD) brain. Elevated levels seen in
breast and colon carcinomas, and which correlates with tumor
progression and invasiveness or risk of progression.
{ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:23403623}.
-!- INDUCTION: By type I interferons. {ECO:0000269|PubMed:1695551}.
-!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues.
Autophosphorylation of Thr-451 is dependent on Thr-446 and is
stimulated by dsRNA binding and dimerization. Autophosphorylation
apparently leads to the activation of the kinase. Tyrosine
autophosphorylation is essential for efficient dsRNA-binding,
dimerization, and kinase activation. {ECO:0000269|PubMed:11152499,
ECO:0000269|PubMed:11337501, ECO:0000269|PubMed:16179258,
ECO:0000269|PubMed:16373505, ECO:0000269|PubMed:20685959,
ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr
protein kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/prkr/";
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/EIF2AK2ID41866ch2p22.html";
-----------------------------------------------------------------------
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EMBL; M35663; AAA36409.1; -; mRNA.
EMBL; M85294; AAA18253.1; -; mRNA.
EMBL; U50648; AAC50768.1; -; Genomic_DNA.
EMBL; U50634; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50635; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50636; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50637; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50638; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50639; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50640; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50641; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50642; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50643; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50644; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50645; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50646; AAC50768.1; JOINED; Genomic_DNA.
EMBL; U50647; AAC50768.1; JOINED; Genomic_DNA.
EMBL; AF167472; AAF13156.1; -; Genomic_DNA.
EMBL; AF167460; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167462; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167463; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167464; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167465; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167466; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167468; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AF167470; AAF13156.1; JOINED; Genomic_DNA.
EMBL; AY302136; AAP57628.1; -; mRNA.
EMBL; AK290655; BAF83344.1; -; mRNA.
EMBL; AK313818; BAG36554.1; -; mRNA.
EMBL; AY228338; AAO38055.1; -; Genomic_DNA.
EMBL; AC007899; AAY24317.1; -; Genomic_DNA.
EMBL; CH471053; EAX00407.1; -; Genomic_DNA.
EMBL; CH471053; EAX00408.1; -; Genomic_DNA.
EMBL; CH471053; EAX00409.1; -; Genomic_DNA.
EMBL; BC093676; AAH93676.1; -; mRNA.
EMBL; BC101475; AAI01476.1; -; mRNA.
CCDS; CCDS1786.1; -. [P19525-1]
CCDS; CCDS46259.1; -. [P19525-2]
PIR; JC5225; JC5225.
RefSeq; NP_001129123.1; NM_001135651.2. [P19525-1]
RefSeq; NP_001129124.1; NM_001135652.2. [P19525-2]
RefSeq; NP_002750.1; NM_002759.3. [P19525-1]
RefSeq; XP_011531289.1; XM_011532987.2. [P19525-1]
PDB; 1QU6; NMR; -; A=1-170.
PDB; 2A19; X-ray; 2.50 A; B/C=258-550.
PDB; 2A1A; X-ray; 2.80 A; B=258-550.
PDB; 3UIU; X-ray; 2.90 A; A/B=254-551.
PDBsum; 1QU6; -.
PDBsum; 2A19; -.
PDBsum; 2A1A; -.
PDBsum; 3UIU; -.
SMR; P19525; -.
BioGrid; 111596; 188.
DIP; DIP-2657N; -.
IntAct; P19525; 75.
MINT; P19525; -.
STRING; 9606.ENSP00000233057; -.
BindingDB; P19525; -.
ChEMBL; CHEMBL5785; -.
GuidetoPHARMACOLOGY; 2016; -.
iPTMnet; P19525; -.
PhosphoSitePlus; P19525; -.
SwissPalm; P19525; -.
BioMuta; EIF2AK2; -.
DMDM; 125527; -.
EPD; P19525; -.
jPOST; P19525; -.
MaxQB; P19525; -.
PaxDb; P19525; -.
PeptideAtlas; P19525; -.
PRIDE; P19525; -.
ProteomicsDB; 19391; -.
ProteomicsDB; 53670; -. [P19525-1]
TopDownProteomics; P19525-1; -. [P19525-1]
DNASU; 5610; -.
Ensembl; ENST00000233057; ENSP00000233057; ENSG00000055332. [P19525-1]
Ensembl; ENST00000395127; ENSP00000378559; ENSG00000055332. [P19525-1]
Ensembl; ENST00000405334; ENSP00000385014; ENSG00000055332. [P19525-2]
Ensembl; ENST00000647926; ENSP00000497534; ENSG00000055332. [P19525-1]
GeneID; 5610; -.
KEGG; hsa:5610; -.
UCSC; uc010fab.3; human. [P19525-1]
CTD; 5610; -.
DisGeNET; 5610; -.
GeneCards; EIF2AK2; -.
HGNC; HGNC:9437; EIF2AK2.
HPA; CAB003845; -.
HPA; HPA019795; -.
HPA; HPA063893; -.
MIM; 176871; gene.
neXtProt; NX_P19525; -.
OpenTargets; ENSG00000055332; -.
PharmGKB; PA33779; -.
eggNOG; KOG1033; Eukaryota.
eggNOG; ENOG410XS0B; LUCA.
GeneTree; ENSGT00940000160736; -.
HOGENOM; HOG000234351; -.
InParanoid; P19525; -.
KO; K16195; -.
OMA; ELLYICP; -.
OrthoDB; 1189098at2759; -.
PhylomeDB; P19525; -.
TreeFam; TF317576; -.
Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
Reactome; R-HSA-169131; Inhibition of PKR.
SignaLink; P19525; -.
SIGNOR; P19525; -.
ChiTaRS; EIF2AK2; human.
EvolutionaryTrace; P19525; -.
GeneWiki; Protein_kinase_R; -.
GenomeRNAi; 5610; -.
PMAP-CutDB; P19525; -.
PRO; PR:P19525; -.
Proteomes; UP000005640; Chromosome 2.
Bgee; ENSG00000055332; Expressed in 238 organ(s), highest expression level in oviduct epithelium.
ExpressionAtlas; P19525; baseline and differential.
Genevisible; P19525; HS.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0022626; C:cytosolic ribosome; IBA:GO_Central.
GO; GO:0016020; C:membrane; HDA:UniProtKB.
GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
GO; GO:0005840; C:ribosome; TAS:AgBase.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI.
GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IMP:UniProtKB.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
GO; GO:0019888; F:protein phosphatase regulator activity; TAS:ProtInc.
GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
GO; GO:0000186; P:activation of MAPKK activity; IMP:UniProtKB.
GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
GO; GO:0030683; P:evasion or tolerance by virus of host immune response; TAS:Reactome.
GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
GO; GO:0033689; P:negative regulation of osteoblast proliferation; IMP:UniProtKB.
GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB.
GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB.
GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB.
GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
GO; GO:0035455; P:response to interferon-alpha; IDA:UniProtKB.
GO; GO:0009615; P:response to virus; IMP:UniProtKB.
GO; GO:0006412; P:translation; IEA:Ensembl.
CDD; cd00048; DSRM; 2.
InterPro; IPR014720; dsRBD_dom.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR008271; Ser/Thr_kinase_AS.
Pfam; PF00035; dsrm; 2.
Pfam; PF00069; Pkinase; 1.
SMART; SM00358; DSRM; 2.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS50137; DS_RBD; 2.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; Antiviral defense;
ATP-binding; Complete proteome; Cytoplasm; Direct protein sequencing;
Host-virus interaction; Immunity; Innate immunity; Isopeptide bond;
Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
Reference proteome; Repeat; RNA-binding;
Serine/threonine-protein kinase; Transcription;
Transcription regulation; Transferase; Tyrosine-protein kinase;
Ubl conjugation.
INIT_MET 1 1 Removed. {ECO:0000244|PubMed:22223895,
ECO:0000244|PubMed:22814378,
ECO:0000269|Ref.13}.
CHAIN 2 551 Interferon-induced, double-stranded RNA-
activated protein kinase.
/FTId=PRO_0000085945.
DOMAIN 9 77 DRBM 1. {ECO:0000255|PROSITE-
ProRule:PRU00266}.
DOMAIN 100 167 DRBM 2. {ECO:0000255|PROSITE-
ProRule:PRU00266}.
DOMAIN 267 538 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
REPEAT 331 343 1.
REPEAT 345 357 2.
NP_BIND 273 281 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
REGION 266 551 Interaction with TRAF5.
{ECO:0000269|PubMed:15121867}.
REGION 331 357 2 X 13 AA approximate repeats.
ACT_SITE 414 414 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10027}.
BINDING 296 296 ATP.
MOD_RES 2 2 N-acetylalanine.
{ECO:0000244|PubMed:22223895,
ECO:0000244|PubMed:22814378,
ECO:0000269|Ref.13}.
MOD_RES 83 83 Phosphoserine.
{ECO:0000244|PubMed:18669648,
ECO:0000244|PubMed:19690332,
ECO:0000244|PubMed:20068231,
ECO:0000269|PubMed:11152499}.
MOD_RES 88 88 Phosphothreonine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 89 89 Phosphothreonine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 90 90 Phosphothreonine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 101 101 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:16373505}.
MOD_RES 162 162 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:16373505}.
MOD_RES 242 242 Phosphoserine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 255 255 Phosphothreonine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 258 258 Phosphothreonine; by autocatalysis.
{ECO:0000305|PubMed:11152499}.
MOD_RES 293 293 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:16373505}.
MOD_RES 446 446 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:11337501,
ECO:0000269|PubMed:16179258}.
MOD_RES 451 451 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:11337501,
ECO:0000269|PubMed:20685959}.
MOD_RES 456 456 Phosphoserine.
{ECO:0000244|PubMed:18669648}.
MOD_RES 542 542 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
CROSSLNK 69 69 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ISG15).
{ECO:0000269|PubMed:23229543}.
CROSSLNK 159 159 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ISG15).
{ECO:0000269|PubMed:23229543}.
VAR_SEQ 263 303 Missing (in isoform 2).
{ECO:0000303|Ref.7}.
/FTId=VSP_046177.
VARIANT 428 428 V -> E (in dbSNP:rs56219559).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_040474.
VARIANT 439 439 L -> V (in a lung adenocarcinoma sample;
somatic mutation).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_040475.
VARIANT 506 506 I -> V (in dbSNP:rs34821155).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_040476.
MUTAGEN 59 60 SK->AA: In FL-PKR-2AI; moderate loss of
activity but no effect on dsRNA binding.
{ECO:0000269|PubMed:11337501}.
MUTAGEN 60 60 K->A: Impairs dsRNA binding but not
dimerization or activity.
{ECO:0000269|PubMed:11337501}.
MUTAGEN 67 67 A->E: Significant loss of activity; loss
of dsRNA binding and dimerization.
{ECO:0000269|PubMed:11337501}.
MUTAGEN 83 83 S->A: No effect on enzymatic activity;
when associated with A-88; A-89 and A-90.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 88 88 T->A: No effect on enzymatic activity;
when associated with A-83; A-89 and A-90.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 89 89 T->A: No effect on enzymatic activity;
when associated with A-83; A-88 and A-90.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 90 90 T->A: No effect on enzymatic activity;
when associated with A-83; A-88 and A-89.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 149 150 TK->AA: In FL-PKR-2AII; no effect on
activity. {ECO:0000269|PubMed:11337501}.
MUTAGEN 242 242 S->A: Moderate loss of activity; when
associated with A-255 and A-258.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 244 296 Missing: Loss of activity.
{ECO:0000269|PubMed:11337501}.
MUTAGEN 255 255 T->A: Moderate loss of activity; when
associated with A-242 and A-255.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 258 258 T->A: Moderate loss of activity.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 296 296 K->R: Loss of activity.
{ECO:0000269|PubMed:11152499}.
MUTAGEN 446 446 T->A: Significant loss of activity and
impairs autophosphorylation of T-451.
{ECO:0000269|PubMed:11337501}.
MUTAGEN 451 451 T->A: Loss of activity.
{ECO:0000269|PubMed:11337501}.
CONFLICT 102 102 I -> M (in Ref. 7; AAP57628).
{ECO:0000305}.
CONFLICT 224 224 S -> R (in Ref. 7; AAP57628).
{ECO:0000305}.
CONFLICT 512 512 K -> E (in Ref. 6; AAF13156).
{ECO:0000305}.
STRAND 5 7 {ECO:0000244|PDB:1QU6}.
HELIX 10 21 {ECO:0000244|PDB:1QU6}.
STRAND 26 32 {ECO:0000244|PDB:1QU6}.
TURN 35 37 {ECO:0000244|PDB:1QU6}.
STRAND 41 50 {ECO:0000244|PDB:1QU6}.
STRAND 54 56 {ECO:0000244|PDB:1QU6}.
HELIX 61 76 {ECO:0000244|PDB:1QU6}.
HELIX 102 111 {ECO:0000244|PDB:1QU6}.
STRAND 115 123 {ECO:0000244|PDB:1QU6}.
STRAND 125 138 {ECO:0000244|PDB:1QU6}.
STRAND 144 149 {ECO:0000244|PDB:1QU6}.
HELIX 150 167 {ECO:0000244|PDB:1QU6}.
HELIX 261 266 {ECO:0000244|PDB:2A19}.
STRAND 267 274 {ECO:0000244|PDB:2A19}.
STRAND 276 278 {ECO:0000244|PDB:2A19}.
STRAND 281 286 {ECO:0000244|PDB:2A19}.
TURN 287 289 {ECO:0000244|PDB:2A19}.
STRAND 292 299 {ECO:0000244|PDB:2A19}.
HELIX 303 305 {ECO:0000244|PDB:2A19}.
HELIX 306 314 {ECO:0000244|PDB:2A19}.
STRAND 323 332 {ECO:0000244|PDB:2A19}.
STRAND 358 366 {ECO:0000244|PDB:2A19}.
HELIX 374 380 {ECO:0000244|PDB:2A19}.
HELIX 381 383 {ECO:0000244|PDB:2A19}.
HELIX 388 407 {ECO:0000244|PDB:2A19}.
STRAND 410 412 {ECO:0000244|PDB:2A1A}.
HELIX 417 419 {ECO:0000244|PDB:2A19}.
STRAND 420 424 {ECO:0000244|PDB:2A19}.
STRAND 427 430 {ECO:0000244|PDB:2A19}.
STRAND 437 440 {ECO:0000244|PDB:2A19}.
HELIX 457 461 {ECO:0000244|PDB:2A19}.
HELIX 468 482 {ECO:0000244|PDB:2A19}.
HELIX 488 499 {ECO:0000244|PDB:2A19}.
STRAND 505 507 {ECO:0000244|PDB:3UIU}.
HELIX 509 518 {ECO:0000244|PDB:2A19}.
HELIX 523 525 {ECO:0000244|PDB:2A19}.
HELIX 529 539 {ECO:0000244|PDB:2A19}.
SEQUENCE 551 AA; 62094 MW; 815AD83ACAB45DA3 CRC64;
MAGDLSAGFF MEELNTYRQK QGVVLKYQEL PNSGPPHDRR FTFQVIIDGR EFPEGEGRSK
KEAKNAAAKL AVEILNKEKK AVSPLLLTTT NSSEGLSMGN YIGLINRIAQ KKRLTVNYEQ
CASGVHGPEG FHYKCKMGQK EYSIGTGSTK QEAKQLAAKL AYLQILSEET SVKSDYLSSG
SFATTCESQS NSLVTSTLAS ESSSEGDFSA DTSEINSNSD SLNSSSLLMN GLRNNQRKAK
RSLAPRFDLP DMKETKYTVD KRFGMDFKEI ELIGSGGFGQ VFKAKHRIDG KTYVIKRVKY
NNEKAEREVK ALAKLDHVNI VHYNGCWDGF DYDPETSDDS LESSDYDPEN SKNSSRSKTK
CLFIQMEFCD KGTLEQWIEK RRGEKLDKVL ALELFEQITK GVDYIHSKKL IHRDLKPSNI
FLVDTKQVKI GDFGLVTSLK NDGKRTRSKG TLRYMSPEQI SSQDYGKEVD LYALGLILAE
LLHVCDTAFE TSKFFTDLRD GIISDIFDKK EKTLLQKLLS KKPEDRPNTS EILRTLTVWK
KSPEKNERHT C


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