E2AK4_MOUSE
ID E2AK4_MOUSE Reviewed; 1648 AA.
AC Q9QZ05; A2AUM3; A2AUM4; Q6GQT4; Q6ZPT5; Q8C5S0; Q8CIF5; Q9CT30; Q9CUV9;
AC Q9ESB6; Q9ESB7; Q9ESB8;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=eIF-2-alpha kinase GCN2 {ECO:0000305};
DE AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 4 {ECO:0000312|MGI:MGI:1353427};
DE EC=2.7.11.1 {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:10655230, ECO:0000269|PubMed:16601681};
DE AltName: Full=GCN2-like protein;
DE Short=mGCN2;
GN Name=Eif2ak4 {ECO:0000312|MGI:MGI:1353427}; Synonyms=Gcn2, Kiaa1338;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AUTOPHOSPHORYLATION, DOMAIN, AND TISSUE SPECIFICITY.
RC STRAIN=BALB/cJ;
RX PubMed=10504407; DOI=10.1046/j.1432-1327.1999.00780.x;
RA Berlanga J.J., Santoyo J., de Haro C.;
RT "Characterization of a mammalian homolog of the GCN2 eukaryotic initiation
RT factor 2alpha kinase.";
RL Eur. J. Biochem. 265:754-762(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4), FUNCTION, CATALYTIC
RP ACTIVITY, AUTOPHOSPHORYLATION, DOMAIN, AND TISSUE SPECIFICITY.
RC STRAIN=BALB/cJ;
RX PubMed=10655230; DOI=10.1093/genetics/154.2.787;
RA Sood R., Porter A.C., Olsen D.A., Cavener D.R., Wek R.C.;
RT "A mammalian homologue of GCN2 protein kinase important for translational
RT control by phosphorylation of eukaryotic initiation factor-2alpha.";
RL Genetics 154:787-801(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 6).
RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 248-1648.
RC TISSUE=Embryonic tail;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [7]
RP SEQUENCE REVISION.
RA Okazaki N., Kikuno R., Nagase T., Ohara O., Koga H.;
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP PROTEIN SEQUENCE OF 1053-1061, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [9]
RP FUNCTION, AND AUTOPHOSPHORYLATION.
RX PubMed=11106749; DOI=10.1016/s1097-2765(00)00108-8;
RA Harding H.P., Novoa I., Zhang Y., Zeng H., Wek R., Schapira M., Ron D.;
RT "Regulated translation initiation controls stress-induced gene expression
RT in mammalian cells.";
RL Mol. Cell 6:1099-1108(2000).
RN [10]
RP FUNCTION, AND PHOSPHORYLATION AT THR-898.
RX PubMed=12176355; DOI=10.1016/s0960-9822(02)01037-0;
RA Deng J., Harding H.P., Raught B., Gingras A.C., Berlanga J.J., Scheuner D.,
RA Kaufman R.J., Ron D., Sonenberg N.;
RT "Activation of GCN2 in UV-irradiated cells inhibits translation.";
RL Curr. Biol. 12:1279-1286(2002).
RN [11]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=12215525; DOI=10.1128/mcb.22.19.6681-6688.2002;
RA Zhang P., McGrath B.C., Reinert J., Olsen D.S., Lei L., Gill S., Wek S.A.,
RA Vattem K.M., Wek R.C., Kimball S.R., Jefferson L.S., Cavener D.R.;
RT "The GCN2 eIF2alpha kinase is required for adaptation to amino acid
RT deprivation in mice.";
RL Mol. Cell. Biol. 22:6681-6688(2002).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15213227; DOI=10.1074/jbc.m404559200;
RA Anthony T.G., McDaniel B.J., Byerley R.L., McGrath B.C., Cavener D.R.,
RA McNurlan M.A., Wek R.C.;
RT "Preservation of liver protein synthesis during dietary leucine deprivation
RT occurs at the expense of skeletal muscle mass in mice deleted for eIF2
RT kinase GCN2.";
RL J. Biol. Chem. 279:36553-36561(2004).
RN [13]
RP FUNCTION, DISRUPTION PHENOTYPE, AND CONDITIONAL KNOCKOUT IN BRAIN.
RX PubMed=16054071; DOI=10.1016/j.cmet.2005.03.004;
RA Maurin A.C., Jousse C., Averous J., Parry L., Bruhat A., Cherasse Y.,
RA Zeng H., Zhang Y., Harding H.P., Ron D., Fafournoux P.;
RT "The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis
RT in omnivores.";
RL Cell Metab. 1:273-277(2005).
RN [14]
RP FUNCTION.
RX PubMed=16176978; DOI=10.1091/mbc.e05-03-0268;
RA Hamanaka R.B., Bennett B.S., Cullinan S.B., Diehl J.A.;
RT "PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle
RT arrest after activation of the unfolded protein response pathway.";
RL Mol. Biol. Cell 16:5493-5501(2005).
RN [15]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=16121183; DOI=10.1038/nature03897;
RA Costa-Mattioli M., Gobert D., Harding H., Herdy B., Azzi M., Bruno M.,
RA Bidinosti M., Ben Mamou C., Marcinkiewicz E., Yoshida M., Imataka H.,
RA Cuello A.C., Seidah N., Sossin W., Lacaille J.C., Ron D., Nader K.,
RA Sonenberg N.;
RT "Translational control of hippocampal synaptic plasticity and memory by the
RT eIF2alpha kinase GCN2.";
RL Nature 436:1166-1173(2005).
RN [16]
RP FUNCTION.
RX PubMed=15774759; DOI=10.1126/science.1104882;
RA Hao S., Sharp J.W., Ross-Inta C.M., McDaniel B.J., Anthony T.G., Wek R.C.,
RA Cavener D.R., McGrath B.C., Rudell J.B., Koehnle T.J., Gietzen D.W.;
RT "Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform
RT cortex.";
RL Science 307:1776-1778(2005).
RN [17]
RP FUNCTION (MICROBIAL INFECTION), CATALYTIC ACTIVITY, ACTIVITY REGULATION
RP (MICROBIAL INFECTION), AUTOPHOSPHORYLATION, DISRUPTION PHENOTYPE, AND
RP MUTAGENESIS OF LYS-618; PHE-1142 AND ARG-1143.
RX PubMed=16601681; DOI=10.1038/sj.emboj.7601073;
RA Berlanga J.J., Ventoso I., Harding H.P., Deng J., Ron D., Sonenberg N.,
RA Carrasco L., de Haro C.;
RT "Antiviral effect of the mammalian translation initiation factor 2alpha
RT kinase GCN2 against RNA viruses.";
RL EMBO J. 25:1730-1740(2006).
RN [18]
RP FUNCTION.
RX PubMed=19797084; DOI=10.1128/mcb.01044-09;
RA Raveh-Amit H., Maissel A., Poller J., Marom L., Elroy-Stein O., Shapira M.,
RA Livneh E.;
RT "Translational control of protein kinase Ceta by two upstream open reading
RT frames.";
RL Mol. Cell. Biol. 29:6140-6148(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [20]
RP FUNCTION.
RX PubMed=20660158; DOI=10.1091/mbc.e10-01-0023;
RA Muaddi H., Majumder M., Peidis P., Papadakis A.I., Holcik M., Scheuner D.,
RA Kaufman R.J., Hatzoglou M., Koromilas A.E.;
RT "Phosphorylation of eIF2alpha at serine 51 is an important determinant of
RT cell survival and adaptation to glucose deficiency.";
RL Mol. Biol. Cell 21:3220-3231(2010).
RN [21]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23447528; DOI=10.1074/jbc.m113.461970;
RA Roffe M., Hajj G.N., Azevedo H.F., Alves V.S., Castilho B.A.;
RT "IMPACT is a developmentally regulated protein in neurons that opposes the
RT eukaryotic initiation factor 2alpha kinase GCN2 in the modulation of
RT neurite outgrowth.";
RL J. Biol. Chem. 288:10860-10869(2013).
RN [22]
RP INTERACTION WITH GCN1, AND PHOSPHORYLATION AT THR-898.
RX PubMed=24333428; DOI=10.1016/j.bbrc.2013.12.021;
RA Cambiaghi T.D., Pereira C.M., Shanmugam R., Bolech M., Wek R.C.,
RA Sattlegger E., Castilho B.A.;
RT "Evolutionarily conserved IMPACT impairs various stress responses that
RT require GCN1 for activating the eIF2 kinase GCN2.";
RL Biochem. Biophys. Res. Commun. 443:592-597(2014).
RN [23]
RP FUNCTION (MICROBIAL INFECTION), AND DISRUPTION PHENOTYPE.
RX PubMed=24310610; DOI=10.1126/science.1246829;
RA Ravindran R., Khan N., Nakaya H.I., Li S., Loebbermann J., Maddur M.S.,
RA Park Y., Jones D.P., Chappert P., Davoust J., Weiss D.S., Virgin H.W.,
RA Ron D., Pulendran B.;
RT "Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances
RT antigen presentation.";
RL Science 343:313-317(2014).
RN [24]
RP INTERACTION WITH DNAJC3.
RX PubMed=25329545; DOI=10.1042/bj20140852;
RA Roobol A., Roobol J., Bastide A., Knight J.R., Willis A.E., Smales C.M.;
RT "p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization
RT and expression underpin protein synthesis and ER processing capacity.";
RL Biochem. J. 465:213-225(2015).
RN [25]
RP FUNCTION.
RX PubMed=26102367; DOI=10.1371/journal.pgen.1005212;
RA Lehman S.L., Cerniglia G.J., Johannes G.J., Ye J., Ryeom S., Koumenis C.;
RT "Translational Upregulation of an Individual p21Cip1 Transcript Variant by
RT GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress.";
RL PLoS Genet. 11:E1005212-E1005212(2015).
RN [26]
RP STRUCTURE BY NMR OF 17-107.
RX PubMed=15273307; DOI=10.1110/ps.04751804;
RA Nameki N., Yoneyama M., Koshiba S., Tochio N., Inoue M., Seki E.,
RA Matsuda T., Tomo Y., Harada T., Saito K., Kobayashi N., Yabuki T., Aoki M.,
RA Nunokawa E., Matsuda N., Sakagami N., Terada T., Shirouzu M., Yoshida M.,
RA Hirota H., Osanai T., Tanaka A., Arakawa T., Carninci P., Kawai J.,
RA Hayashizaki Y., Kinoshita K., Guntert P., Kigawa T., Yokoyama S.;
RT "Solution structure of the RWD domain of the mouse GCN2 protein.";
RL Protein Sci. 13:2089-2100(2004).
CC -!- FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates
CC the alpha subunit of eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) in response to low amino acid availability
CC (PubMed:10504407, PubMed:10655230, PubMed:12176355, PubMed:12215525,
CC PubMed:15213227, PubMed:16054071, PubMed:16176978, PubMed:16121183,
CC PubMed:15774759, PubMed:16601681, PubMed:26102367). Plays a role as an
CC activator of the integrated stress response (ISR) required for
CC adaptation to amino acid starvation (PubMed:10655230, PubMed:11106749,
CC PubMed:12176355, PubMed:15213227, PubMed:16176978, PubMed:26102367).
CC EIF2S1/eIF-2-alpha phosphorylation in response to stress converts
CC EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading
CC to a global attenuation of cap-dependent translation, and thus to a
CC reduced overall utilization of amino acids, while concomitantly
CC initiating the preferential translation of ISR-specific mRNAs, such as
CC the transcriptional activator ATF4, and hence allowing ATF4-mediated
CC reprogramming of amino acid biosynthetic gene expression to alleviate
CC nutrient depletion (PubMed:10655230, PubMed:11106749, PubMed:12176355,
CC PubMed:15213227, PubMed:16176978, PubMed:26102367). Required for the
CC translational induction of protein kinase PRKCH following amino acid
CC starvation (PubMed:19797084). Binds uncharged tRNAs (By similarity).
CC Involved in cell cycle arrest by promoting cyclin D1 mRNA translation
CC repression after the unfolded protein response pathway (UPR) activation
CC or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in
CC response to amino acid deprivation (PubMed:16176978, PubMed:26102367).
CC Plays a role in the consolidation of synaptic plasticity, learning as
CC well as formation of long-term memory (PubMed:16121183). Plays a role
CC in neurite outgrowth inhibition (PubMed:23447528). Plays a role in
CC feeding behavior to maintain amino acid homeostasis; contributes to the
CC innate aversion toward diets of imbalanced amino acid composition
CC (PubMed:16054071, PubMed:15774759). Plays a proapoptotic role in
CC response to glucose deprivation (PubMed:20660158). Promotes global
CC cellular protein synthesis repression in response to UV irradiation
CC independently of the stress-activated protein kinase/c-Jun N-terminal
CC kinase (SAPK/JNK) and p38 MAPK signaling pathways (PubMed:12176355).
CC {ECO:0000250|UniProtKB:P15442, ECO:0000269|PubMed:10504407,
CC ECO:0000269|PubMed:10655230, ECO:0000269|PubMed:11106749,
CC ECO:0000269|PubMed:12176355, ECO:0000269|PubMed:12215525,
CC ECO:0000269|PubMed:15213227, ECO:0000269|PubMed:15774759,
CC ECO:0000269|PubMed:16054071, ECO:0000269|PubMed:16121183,
CC ECO:0000269|PubMed:16176978, ECO:0000269|PubMed:16601681,
CC ECO:0000269|PubMed:19797084, ECO:0000269|PubMed:20660158,
CC ECO:0000269|PubMed:23447528, ECO:0000269|PubMed:26102367}.
CC -!- FUNCTION: (Microbial infection) Plays a role in the antiviral response
CC against alphavirus infection; impairs early viral mRNA translation of
CC the incoming genomic virus RNA, thus preventing alphavirus replication.
CC {ECO:0000269|PubMed:16601681}.
CC -!- FUNCTION: (Microbial infection) Plays a role in modulating the adaptive
CC immune response to Yellow fever virus infection; promotes dendritic
CC cells to initiate autophagy and antigene presentation to both CD4(+)
CC and CD8(+) T-cells under amino acid starvation.
CC {ECO:0000269|PubMed:24310610}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:10655230,
CC ECO:0000269|PubMed:16601681};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:10504407,
CC ECO:0000269|PubMed:10655230, ECO:0000269|PubMed:16601681};
CC -!- ACTIVITY REGULATION: (Microbial infection) Kinase activity is enhanced
CC by alphavirus genomic RNA sequences (PubMed:16601681). Kinase activity
CC is stimulated upon binding to uncharged tRNAs (PubMed:16601681).
CC Activated by serum starvation (in vitro) (PubMed:10504407).
CC {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:16601681}.
CC -!- SUBUNIT: Homodimer; homodimerization is important for kinase activation
CC by uncharged tRNAs (By similarity). Interacts with GCN1; this
CC interaction stimulates EIF2AK4/GCN2 kinase activity and is impaired by
CC IMPACT upon a variety of stress conditions, such as amino acid
CC depletion, UV-C irradiation, proteasome inhibitor treatment and glucose
CC deprivation (PubMed:24333428). Interacts with DNAJC3; this interaction
CC inhibits EIF2AK4/GCN2 kinase activity during endoplasmic reticulum
CC (ER), hypothermic and amino acid-starving stress conditions
CC (PubMed:25329545). {ECO:0000250|UniProtKB:P15442,
CC ECO:0000269|PubMed:24333428, ECO:0000269|PubMed:25329545}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:23447528}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=GCN2beta;
CC IsoId=Q9QZ05-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9QZ05-2; Sequence=VSP_013042, VSP_013045;
CC Name=3; Synonyms=GCN2gamma;
CC IsoId=Q9QZ05-3; Sequence=VSP_013043, VSP_013044;
CC Name=4; Synonyms=GCN2alpha;
CC IsoId=Q9QZ05-4; Sequence=VSP_013040;
CC Name=5;
CC IsoId=Q9QZ05-5; Sequence=VSP_013039, VSP_013048, VSP_013049,
CC VSP_013050;
CC Name=6;
CC IsoId=Q9QZ05-6; Sequence=VSP_013041, VSP_013046, VSP_013047;
CC -!- TISSUE SPECIFICITY: Expressed in liver (PubMed:10504407). Expressed
CC predominantly in the hippocampal CA1 region and the dentate gyrus, and
CC to a lesser degree in CA3 (at protein level) (PubMed:16121183).
CC Expressed in liver, lung, brain, kidney, skeletal muscle and testis
CC (PubMed:10504407, PubMed:10655230). Expressed weakly in heart and
CC spleen (PubMed:10655230). Expressed in the hippocampal CA1 and CA3
CC regions, the dentate gyrus and cerebellum (PubMed:16121183). Isoform 1
CC is widely expressed (PubMed:12215525). Isoform 1 is expressed in brain,
CC liver, skeletal muscle and testis (PubMed:10655230). Isoform 3 is
CC expressed in lung, brain, testis, prostate and choroid plexus
CC (PubMed:12215525). Isoform 4 is expressed in muscle, lung, kidney,
CC brain, testis and prostate (PubMed:10655230, PubMed:12215525).
CC {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:10655230,
CC ECO:0000269|PubMed:12215525, ECO:0000269|PubMed:16121183}.
CC -!- DOMAIN: The histidyl-tRNA synthetase-like region and protein kinase
CC domains are necessary for eIF-2-alpha kinase activity and eIF-2-alpha-
CC mediated translational control (PubMed:10655230). The histidyl-tRNA
CC synthetase-like domain is necessary for binding to uncharged tRNAs
CC (PubMed:16601681). Kinase domain 1 is a degenerate kinase domain
CC (PubMed:10504407). {ECO:0000269|PubMed:10504407,
CC ECO:0000269|PubMed:10655230}.
CC -!- PTM: Autophosphorylated; autophosphorylation on Thr-898 is increased
CC upon amino acid starvation and in UV irradiation cells and inhibited in
CC presence of IMPACT (PubMed:10504407, PubMed:10655230, PubMed:11106749,
CC PubMed:12176355, PubMed:16601681, PubMed:24333428).
CC {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:10655230,
CC ECO:0000269|PubMed:11106749, ECO:0000269|PubMed:12176355,
CC ECO:0000269|PubMed:16601681, ECO:0000269|PubMed:24333428}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable, fertile, and exhibit no
CC phenotypic abnormalities under standard growth conditions
CC (PubMed:12215525). Show an increase in prenatal and neonatal
CC mortalities when essential amino acids are absent in the maternal diet
CC during gestation (PubMed:12215525, PubMed:15213227). In response to
CC nutrient deprivation, display reduced abilities to chronically down-
CC regulate hepatic protein synthesis, resulting in preservation of liver
CC mass relative to body size and enhanced skeletal muscle loss
CC (PubMed:15213227). Mice exhibit a lowered threshold for the induction
CC of strong and robust long-term potentiation (LTP) in the CA1 neurons of
CC the hippocampus and the consolidation of long-term memory
CC (PubMed:16121183). Knockout and conditional knockout in the brain
CC result in a diminution of the rate of food consumption and an
CC impairment in the food aversion response in mice fed an imbalanced
CC amino acid diet (PubMed:16054071). Mice are more susceptible to
CC intranasal Sindbis virus infection, with high virus titers in the brain
CC compared to similarly infected control animals (PubMed:16601681). Mice
CC infected with yellow fever virus show a decrease in dendritic cell
CC autophagy and an impairment in their capacity to present antigens to T-
CC cells under amino acid starvation (PubMed:24310610).
CC {ECO:0000269|PubMed:12215525, ECO:0000269|PubMed:15213227,
CC ECO:0000269|PubMed:16054071, ECO:0000269|PubMed:16121183,
CC ECO:0000269|PubMed:16601681, ECO:0000269|PubMed:24310610}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC ---------------------------------------------------------------------------
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DR EMBL; AJ243533; CAB58363.1; -; mRNA.
DR EMBL; AF193342; AAG22589.1; -; mRNA.
DR EMBL; AF193343; AAG22590.1; -; mRNA.
DR EMBL; AF193344; AAG22591.1; -; mRNA.
DR EMBL; AK011380; BAB27580.1; -; mRNA.
DR EMBL; AK013758; BAB28984.1; -; mRNA.
DR EMBL; AK077199; BAC36677.1; -; mRNA.
DR EMBL; AL929163; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC023958; AAH23958.1; -; mRNA.
DR EMBL; BC072637; AAH72637.1; -; mRNA.
DR EMBL; AK129334; BAC98144.2; -; Transcribed_RNA.
DR CCDS; CCDS16576.1; -. [Q9QZ05-1]
DR CCDS; CCDS50669.1; -. [Q9QZ05-2]
DR RefSeq; NP_001171277.1; NM_001177806.1. [Q9QZ05-2]
DR RefSeq; NP_038747.2; NM_013719.3.
DR RefSeq; XP_006499688.1; XM_006499625.3. [Q9QZ05-2]
DR PDB; 1UKX; NMR; -; A=17-139.
DR PDB; 4OTN; X-ray; 1.90 A; A/B=1514-1648.
DR PDBsum; 1UKX; -.
DR PDBsum; 4OTN; -.
DR AlphaFoldDB; Q9QZ05; -.
DR SMR; Q9QZ05; -.
DR BioGRID; 205123; 3.
DR STRING; 10090.ENSMUSP00000005233; -.
DR iPTMnet; Q9QZ05; -.
DR PhosphoSitePlus; Q9QZ05; -.
DR EPD; Q9QZ05; -.
DR jPOST; Q9QZ05; -.
DR MaxQB; Q9QZ05; -.
DR PaxDb; Q9QZ05; -.
DR PeptideAtlas; Q9QZ05; -.
DR PRIDE; Q9QZ05; -.
DR ProteomicsDB; 279597; -. [Q9QZ05-1]
DR ProteomicsDB; 279598; -. [Q9QZ05-2]
DR ProteomicsDB; 279599; -. [Q9QZ05-3]
DR ProteomicsDB; 279600; -. [Q9QZ05-4]
DR ProteomicsDB; 279601; -. [Q9QZ05-5]
DR ProteomicsDB; 279602; -. [Q9QZ05-6]
DR Antibodypedia; 22934; 430 antibodies from 37 providers.
DR DNASU; 27103; -.
DR Ensembl; ENSMUST00000102527; ENSMUSP00000099586; ENSMUSG00000005102. [Q9QZ05-2]
DR Ensembl; ENSMUST00000110869; ENSMUSP00000106493; ENSMUSG00000005102. [Q9QZ05-5]
DR Ensembl; ENSMUST00000110870; ENSMUSP00000106494; ENSMUSG00000005102. [Q9QZ05-4]
DR GeneID; 27103; -.
DR KEGG; mmu:27103; -.
DR UCSC; uc008lrx.2; mouse. [Q9QZ05-2]
DR UCSC; uc008lry.1; mouse. [Q9QZ05-1]
DR UCSC; uc008lrz.1; mouse. [Q9QZ05-5]
DR CTD; 440275; -.
DR MGI; MGI:1353427; Eif2ak4.
DR VEuPathDB; HostDB:ENSMUSG00000005102; -.
DR eggNOG; KOG1035; Eukaryota.
DR GeneTree; ENSGT00940000156798; -.
DR HOGENOM; CLU_001222_1_0_1; -.
DR InParanoid; Q9QZ05; -.
DR OMA; GSEMIYE; -.
DR OrthoDB; 64059at2759; -.
DR PhylomeDB; Q9QZ05; -.
DR BRENDA; 2.7.11.20; 3474.
DR BioGRID-ORCS; 27103; 8 hits in 80 CRISPR screens.
DR ChiTaRS; Eif2ak4; mouse.
DR EvolutionaryTrace; Q9QZ05; -.
DR PRO; PR:Q9QZ05; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9QZ05; protein.
DR Bgee; ENSMUSG00000005102; Expressed in renal medulla collecting duct and 230 other tissues.
DR ExpressionAtlas; Q9QZ05; baseline and differential.
DR Genevisible; Q9QZ05; MM.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0022626; C:cytosolic ribosome; ISS:UniProtKB.
DR GO; GO:0005844; C:polysome; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0071074; F:eukaryotic initiation factor eIF2 binding; IC:ParkinsonsUK-UCL.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0000049; F:tRNA binding; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IDA:UniProtKB.
DR GO; GO:0070417; P:cellular response to cold; ISS:UniProtKB.
DR GO; GO:1990253; P:cellular response to leucine starvation; IDA:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; IDA:MGI.
DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0000077; P:DNA damage checkpoint signaling; IEA:InterPro.
DR GO; GO:0036492; P:eiF2alpha phosphorylation in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IMP:MGI.
DR GO; GO:0140469; P:GCN2-mediated signaling; IDA:UniProtKB.
DR GO; GO:0007612; P:learning; IMP:UniProtKB.
DR GO; GO:0007616; P:long-term memory; IMP:UniProtKB.
DR GO; GO:0044828; P:negative regulation by host of viral genome replication; IDA:UniProtKB.
DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IMP:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; IGI:MGI.
DR GO; GO:0045947; P:negative regulation of translational initiation; IDA:UniProtKB.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; IDA:UniProtKB.
DR GO; GO:1990138; P:neuron projection extension; IMP:UniProtKB.
DR GO; GO:0002821; P:positive regulation of adaptive immune response; IMP:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IDA:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0071264; P:positive regulation of translational initiation in response to starvation; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0032268; P:regulation of cellular protein metabolic process; IEA:UniProt.
DR GO; GO:0060259; P:regulation of feeding behavior; IMP:UniProtKB.
DR GO; GO:0006446; P:regulation of translational initiation; ISS:UniProtKB.
DR GO; GO:0010998; P:regulation of translational initiation by eIF2 alpha phosphorylation; IDA:UniProtKB.
DR GO; GO:0043558; P:regulation of translational initiation in response to stress; IDA:MGI.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IGI:ParkinsonsUK-UCL.
DR GO; GO:0002286; P:T cell activation involved in immune response; IMP:UniProtKB.
DR GO; GO:0019081; P:viral translation; IDA:UniProtKB.
DR Gene3D; 3.10.110.10; -; 1.
DR Gene3D; 3.30.930.10; -; 1.
DR Gene3D; 3.40.50.800; -; 1.
DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL.
DR InterPro; IPR036621; Anticodon-bd_dom_sf.
DR InterPro; IPR016255; Gcn2.
DR InterPro; IPR041715; HisRS-like_core.
DR InterPro; IPR024435; HisRS-related_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR006575; RWD-domain.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR016135; UBQ-conjugating_enzyme/RWD.
DR Pfam; PF12745; HGTP_anticodon2; 1.
DR Pfam; PF00069; Pkinase; 3.
DR Pfam; PF05773; RWD; 1.
DR Pfam; PF13393; tRNA-synt_His; 1.
DR PIRSF; PIRSF000660; Ser/Thr_PK_GCN2; 1.
DR SMART; SM00591; RWD; 1.
DR SMART; SM00220; S_TKc; 2.
DR SUPFAM; SSF54495; SSF54495; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50908; RWD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activation of host autophagy by virus;
KW Activator; Adaptive immunity; Alternative splicing; Antiviral defense;
KW ATP-binding; Cell cycle; Coiled coil; Cytoplasm; Differentiation;
KW Direct protein sequencing; Growth arrest; Host-virus interaction; Immunity;
KW Kinase; Neurogenesis; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; RNA-binding; Serine/threonine-protein kinase;
KW Stress response; Transferase; Translation regulation; tRNA-binding.
FT CHAIN 1..1648
FT /note="eIF-2-alpha kinase GCN2"
FT /id="PRO_0000085948"
FT DOMAIN 25..137
FT /note="RWD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00179"
FT DOMAIN 286..538
FT /note="Protein kinase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 589..1000
FT /note="Protein kinase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 661..784
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1021..1492
FT /note="Histidyl-tRNA synthetase-like"
FT COILED 146..205
FT /evidence="ECO:0000255"
FT COMPBIAS 705..727
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 760..784
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 846
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 595..603
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 618
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 230
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9P2K8"
FT MOD_RES 666
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9P2K8"
FT MOD_RES 869
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9P2K8"
FT MOD_RES 898
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12176355,
FT ECO:0000269|PubMed:24333428"
FT MOD_RES 903
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 1258
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9P2K8"
FT VAR_SEQ 1..801
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013039"
FT VAR_SEQ 1..278
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:10655230"
FT /id="VSP_013040"
FT VAR_SEQ 1..121
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013041"
FT VAR_SEQ 1..112
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013042"
FT VAR_SEQ 1..78
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10655230"
FT /id="VSP_013043"
FT VAR_SEQ 79..86
FT /note="CPPTYPDV -> MRTQRALL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10655230"
FT /id="VSP_013044"
FT VAR_SEQ 113..120
FT /note="LAKKQCGE -> MPTYIPRC (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013045"
FT VAR_SEQ 607..653
FT /note="QNKLDGCCYAVKRIPINPASRHFRRIKGEVTLLSRLHHENIVRYYNA -> R
FT QGCPQSLLSFLFPFHGLTGLVSILGVEREVNKIRLFEAGSTFTSRS (in isoform
FT 6)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013046"
FT VAR_SEQ 654..1648
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013047"
FT VAR_SEQ 802..840
FT /note="YCEKSTLRDTIDQGLFRDTSRLWRLFREILDGLAYIHEK -> MGEDSSSGH
FT HNPLPLKSGNRVLSSVWEEAVDGLFIVFQQ (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013048"
FT VAR_SEQ 1120..1148
FT /note="PFARYVARNNILNLKRYCIERVFRPRKLD -> SWDAAPLKTRPSQTPPLQP
FT YPGEPHVGNT (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013049"
FT VAR_SEQ 1149..1648
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013050"
FT MUTAGEN 618
FT /note="K->R: Inhibits autophosphorylation, eIF-2-alpha
FT phosphorylation and antiviral activity against Sindbis
FT virus."
FT /evidence="ECO:0000269|PubMed:16601681"
FT MUTAGEN 1142
FT /note="F->L: Decreases autophosphorylation, binding to tRNA
FT and Sindbis virus genomic RNA and eIF-2-alpha
FT phosphorylation in amino acid-starved cells; when
FT associated with I-1143."
FT /evidence="ECO:0000269|PubMed:16601681"
FT MUTAGEN 1143
FT /note="R->I: Decreases autophosphorylation, binding to tRNA
FT and Sindbis virus genomic RNA and eIF-2-alpha
FT phosphorylation in amino acid-starved cells; when
FT associated with L-1142."
FT /evidence="ECO:0000269|PubMed:16601681"
FT CONFLICT 76
FT /note="Q -> R (in Ref. 3; BAB28984)"
FT /evidence="ECO:0000305"
FT CONFLICT 91
FT /note="E -> D (in Ref. 3; BAB28984)"
FT /evidence="ECO:0000305"
FT CONFLICT 262
FT /note="P -> L (in Ref. 3 and 5; AAH23958)"
FT /evidence="ECO:0000305"
FT CONFLICT 517..539
FT /note="KCVCLDDKERWSPQQLLKHSFIN -> NPRRPKRRPQETSQEVWFC (in
FT Ref. 6; BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 682
FT /note="C -> Y (in Ref. 2; AAG22589/AAG22590/AAG22591 and 6;
FT BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 725..727
FT /note="TGQ -> MGE (in Ref. 3)"
FT /evidence="ECO:0000305"
FT CONFLICT 784
FT /note="I -> V (in Ref. 2; AAG22589/AAG22590/AAG22591 and 6;
FT BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 853
FT /note="F -> I (in Ref. 5; AAH72637)"
FT /evidence="ECO:0000305"
FT CONFLICT 882
FT /note="D -> G (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 887
FT /note="G -> R (in Ref. 2; AAG22589/AAG22590/AAG22591 and 6;
FT BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 895
FT /note="G -> C (in Ref. 6; BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 1021
FT /note="I -> T (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1033
FT /note="I -> L (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1038
FT /note="I -> S (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1167
FT /note="T -> A (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1183
FT /note="I -> V (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1275
FT /note="S -> A (in Ref. 3; BAB27580)"
FT /evidence="ECO:0000305"
FT CONFLICT 1283
FT /note="V -> I (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1296
FT /note="D -> E (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1324
FT /note="T -> N (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1363..1364
FT /note="TV -> AL (in Ref. 2; AAG22589/AAG22590)"
FT /evidence="ECO:0000305"
FT CONFLICT 1383
FT /note="A -> V (in Ref. 1; CAB58363 and 6; BAC98144)"
FT /evidence="ECO:0000305"
FT CONFLICT 1388
FT /note="E -> G (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1403
FT /note="V -> A (in Ref. 2; AAG22589/AAG22590/AAG22591)"
FT /evidence="ECO:0000305"
FT CONFLICT 1467
FT /note="E -> G (in Ref. 3; BAB27580)"
FT /evidence="ECO:0000305"
FT CONFLICT 1532..1537
FT /note="NVIVLA -> TVSVIS (in Ref. 2; AAG22589/AAG22590)"
FT /evidence="ECO:0000305"
FT CONFLICT 1540
FT /note="K -> M (in Ref. 3; BAB27580)"
FT /evidence="ECO:0000305"
FT HELIX 19..33
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 35..40
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 55..59
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 72..77
FT /evidence="ECO:0007829|PDB:1UKX"
FT TURN 81..84
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 91..101
FT /evidence="ECO:0007829|PDB:1UKX"
FT HELIX 102..117
FT /evidence="ECO:0007829|PDB:1UKX"
FT HELIX 123..137
FT /evidence="ECO:0007829|PDB:1UKX"
FT STRAND 1532..1536
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1543..1556
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1558..1562
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1563..1565
FT /evidence="ECO:0007829|PDB:4OTN"
FT STRAND 1566..1577
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1580..1586
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1595..1607
FT /evidence="ECO:0007829|PDB:4OTN"
FT HELIX 1613..1626
FT /evidence="ECO:0007829|PDB:4OTN"
FT STRAND 1631..1638
FT /evidence="ECO:0007829|PDB:4OTN"
FT TURN 1639..1642
FT /evidence="ECO:0007829|PDB:4OTN"
FT STRAND 1643..1647
FT /evidence="ECO:0007829|PDB:4OTN"
SQ SEQUENCE 1648 AA; 186487 MW; F27841DDB317EFCB CRC64;
MAGGRGASGR GRAEPQESYS QRQDHELQAL EAIYGSDFQD LRPDARGRVR EPPEINLVLY
PQGLAGEEVY VQVELQVKCP PTYPDVVPEI ELKNAKGLSN ESVNLLKSHL EELAKKQCGE
VMIFELAHHV QSFLSEHNKP PPKSFHEEML ERQAQEKQQR LLEARRKEEQ EQREILHEIQ
RRKEEIKEEK KRKEMAKQER LEITSLTNQD YASKRDPAGH RAAAILHGGS PDFVGNGKAR
TYSSGRSRRE RQYSVCSGEP SPGSCDILHF SVGSPDQLMV HKGRCVGSDE QLGKVVYNAL
ETATGSFVLL HEWVLQWQKM GPCLTSQEKE KIDKCKRQIQ GAETEFSSLV KLSHPNIVRY
FAMNSREEED SIVIDILAEH VSGISLATHL SHSGPVPAHQ LRKYTAQLLA GLDYLHSNSV
VHKVLSASSV LVDAEGTVKI TDYSISKRLA DICKEDVFEQ ARVRFSDSAL PYKTGKKGDV
WRLGLLLLSL SQGQECGEYP VTIPSDLPAD FQDFLKKCVC LDDKERWSPQ QLLKHSFINP
QPKLPLVEQS PEDSGGQDYI ETVIPSNQLP SAAFFSETQK QFSRYFIEFE ELQLLGKGAF
GAVIKVQNKL DGCCYAVKRI PINPASRHFR RIKGEVTLLS RLHHENIVRY YNAWIERHER
PAVPGTPPPD CTPQAQDSPA TCGKTSGDTE ELGSVEAAAP PPILSSSVEW STSAERSTST
RFPVTGQDSS SDEEDEDERD GVFSQSFLPA SDSDSDIIFD NEDENSKSQN QDEDCNQKDG
SHEIEPSVTA EAVHYLYIQM EYCEKSTLRD TIDQGLFRDT SRLWRLFREI LDGLAYIHEK
GMIHRDLKPV NIFLDSDDHV KIGDFGLATD HLAFTAEGKQ DDQAGDGVIK SDPSGHLTGM
VGTALYVSPE VQGSTKSAYN QKVDLFSLGI IFFEMSYHPM VTASERIFVL NQLRDPTSPK
FPDDFDDGEH TKQKSVISWL LNHDPAKRPT AMELLKSELL PPPQMEESEL HEVLHHTLAN
IDGKAYRTMM SQIFCQHISP AIDYTYDSDI LKGNFLIRTA KIQQLVCETI VRVFKRHGAV
QLCTPLLLPR NRQIYEHNEA ALFMDHSGML VMLPFDLRVP FARYVARNNI LNLKRYCIER
VFRPRKLDRF HPKELLECAF DIVTSTTNSS LPTAETIYTI YEIIQEFPAL QERNYSIYLN
HTMLLKAILL HCGIPEDKLS QVYVILYDAV TEKLTRREVE AKFCNLSLSS NSLCRLYKFI
EQKGDLQDLT PTINSLIKQK TGVAQLVKYS LKDLEDVVGL LKKLGVKLQV SINLGLVYKV
QQHTGIIFQF LAFSKRRQRV VPEILAAGGR YDLLIPKFRG PQTVGPVPTA VGVSIAIDKI
FAAVLNMEEP VTVSSCDLLV VSVGQMSMSR AINLTQKLWT AGITAEIMYD WSQSQEELQE
YCRHHEITYV ALVSDKEGSH VKVKSFEKER QTEKRVLESD LVDHVMQKLR TKVGDERNFR
DASDNLAVQT LKGSFSNASG LFEIHGTTVV PNVIVLAPEK LSASTRRRHE IQVQTRLQTT
LANLHQKSSE IEILAVDLPK ETILQFLSLE WDADEQAFNT TVKQLLSRLP KQRYLKLVCD
EIYNIKVEKK VSVLFLYSYR DDYYRILF
