E2AK4_HUMAN
ID E2AK4_HUMAN Reviewed; 1649 AA.
AC Q9P2K8; C9JEC4; Q69YL7; Q6DC97; Q96GN6; Q9H5K1; Q9NSQ3; Q9NSZ5; Q9UJ56;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=eIF-2-alpha kinase GCN2 {ECO:0000250|UniProtKB:Q9QZ05};
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q9QZ05};
DE AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 4 {ECO:0000312|HGNC:HGNC:19687};
DE AltName: Full=GCN2-like protein;
GN Name=EIF2AK4 {ECO:0000312|HGNC:HGNC:19687}; Synonyms=GCN2, KIAA1338;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 821-1649 (ISOFORM 1), AND VARIANT CYS-1306.
RC TISSUE=Muscle, and Uterus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 177-1649.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 196-1649, AND VARIANT LEU-441.
RC TISSUE=Melanoma, and Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 831-1649.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1102-1649, AND TISSUE SPECIFICITY.
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 [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-667, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230 AND THR-667, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-667, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1259, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230 AND THR-667, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230; THR-667 AND THR-871, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [16]
RP INVOLVEMENT IN PVOD2.
RX PubMed=24135949; DOI=10.1378/chest.13-2366;
RA Best D.H., Sumner K.L., Austin E.D., Chung W.K., Brown L.M., Borczuk A.C.,
RA Rosenzweig E.B., Bayrak-Toydemir P., Mao R., Cahill B.C., Tazelaar H.D.,
RA Leslie K.O., Hemnes A.R., Robbins I.M., Elliott C.G.;
RT "EIF2AK4 mutations in pulmonary capillary hemangiomatosis.";
RL Chest 145:231-236(2014).
RN [17]
RP TISSUE SPECIFICITY, AND VARIANTS PVOD2 GLN-585 AND ARG-643.
RX PubMed=24292273; DOI=10.1038/ng.2844;
RA Eyries M., Montani D., Girerd B., Perret C., Leroy A., Lonjou C.,
RA Chelghoum N., Coulet F., Bonnet D., Dorfmueller P., Fadel E., Sitbon O.,
RA Simonneau G., Tregouet D.A., Humbert M., Soubrier F.;
RT "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form
RT of pulmonary hypertension.";
RL Nat. Genet. 46:65-69(2014).
RN [18]
RP FUNCTION (MICROBIAL INFECTION).
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 [19]
RP FUNCTION.
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 [20]
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 [21]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-137; TRP-166; LEU-441; VAL-872;
RP TYR-939; ARG-1060; CYS-1306; ARG-1336 AND HIS-1406.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
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:25329545). Plays a role as an activator of the integrated
CC stress response (ISR) required for adaptation to amino acid starvation
CC (By similarity). EIF2S1/eIF-2-alpha phosphorylation in response to
CC stress converts EIF2S1/eIF-2-alpha into a global protein synthesis
CC inhibitor, leading to a global attenuation of cap-dependent
CC translation, and thus to a reduced overall utilization of amino acids,
CC while concomitantly initiating the preferential translation of ISR-
CC specific mRNAs, such as the transcriptional activator ATF4, and hence
CC allowing ATF4-mediated reprogramming of amino acid biosynthetic gene
CC expression to alleviate nutrient depletion (By similarity). Binds
CC uncharged tRNAs (By similarity). Required for the translational
CC induction of protein kinase PRKCH following amino acid starvation (By
CC similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA
CC translation repression after the unfolded protein response pathway
CC (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation
CC activation in response to amino acid deprivation (PubMed:26102367).
CC Plays a role in the consolidation of synaptic plasticity, learning as
CC well as formation of long-term memory (By similarity). Plays a role in
CC neurite outgrowth inhibition (By similarity). Plays a proapoptotic role
CC in response to glucose deprivation (By similarity). 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 (By similarity).
CC Plays a role in the antiviral response against alphavirus infection;
CC impairs early viral mRNA translation of the incoming genomic virus RNA,
CC thus preventing alphavirus replication (By similarity).
CC {ECO:0000250|UniProtKB:P15442, ECO:0000250|UniProtKB:Q9QZ05,
CC ECO:0000269|PubMed:25329545, ECO:0000269|PubMed:26102367}.
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 (PubMed:24310610).
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:0000250|UniProtKB:Q9QZ05};
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:0000250|UniProtKB:Q9QZ05};
CC -!- SUBUNIT: Homodimer; homodimerization is important for kinase activation
CC by uncharged tRNAs. Interacts with GCN1; this interaction stimulates
CC EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety
CC of stress conditions, such as amino acid depletion, UV-C irradiation,
CC proteasome inhibitor treatment and glucose deprivation. Interacts with
CC DNAJC3; this interaction inhibits EIF2AK4/GCN2 kinase activity during
CC endoplasmic reticulum (ER), hypothermic and amino acid-starving stress
CC conditions. {ECO:0000250|UniProtKB:P15442,
CC ECO:0000250|UniProtKB:Q9QZ05}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9QZ05}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9P2K8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9P2K8-2; Sequence=VSP_013038;
CC Name=3;
CC IsoId=Q9P2K8-3; Sequence=VSP_039185, VSP_039186;
CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:10504407). Expressed in
CC lung, smooth muscle cells and macrophages (PubMed:24292273).
CC {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:24292273}.
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. The histidyl-tRNA synthetase-like
CC domain is necessary for binding to uncharged tRNAs. Kinase domain 1 is
CC a degenerate kinase domain. {ECO:0000250|UniProtKB:Q9QZ05}.
CC -!- PTM: Autophosphorylated; autophosphorylation on Thr-899 is increased
CC upon amino acid starvation and in UV irradiation cells and inhibited in
CC presence of IMPACT. {ECO:0000250|UniProtKB:Q9QZ05}.
CC -!- DISEASE: Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2)
CC [MIM:234810]: A disease characterized by widespread fibrous obstruction
CC and intimal thickening of septal veins and preseptal venules, a low
CC diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and
CC nodular ground-glass opacities, septal lines and lymph node enlargement
CC showed by high-resolution computed tomography of the chest. It is
CC frequently associated with pulmonary capillary dilatation and
CC proliferation, and is a rare and devastating cause of pulmonary
CC hypertension. {ECO:0000269|PubMed:24135949,
CC ECO:0000269|PubMed:24292273}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA92576.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
CC Sequence=BAB15625.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC012377; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC025168; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC009350; AAH09350.2; -; mRNA.
DR EMBL; BC078179; AAH78179.1; -; mRNA.
DR EMBL; AB037759; BAA92576.1; ALT_SEQ; mRNA.
DR EMBL; AL137627; CAB70849.1; -; mRNA.
DR EMBL; AL157497; CAB75678.1; -; mRNA.
DR EMBL; AL832907; CAH10626.1; -; mRNA.
DR EMBL; AK027011; BAB15625.1; ALT_INIT; mRNA.
DR EMBL; AJ243428; CAB58360.1; -; mRNA.
DR CCDS; CCDS42016.1; -. [Q9P2K8-1]
DR PIR; T46924; T46924.
DR RefSeq; NP_001013725.2; NM_001013703.3. [Q9P2K8-1]
DR PDB; 6N3L; X-ray; 2.61 A; A/B=577-657, A/B=782-1013.
DR PDB; 6N3N; X-ray; 3.01 A; A=577-1013.
DR PDB; 6N3O; X-ray; 2.40 A; A=577-1013.
DR PDB; 7E2K; X-ray; 2.04 A; A=17-139.
DR PDB; 7E2M; X-ray; 2.35 A; A/B/C/D/E/F=17-139.
DR PDB; 7QQ6; X-ray; 2.80 A; A/B/C/D=577-1020.
DR PDBsum; 6N3L; -.
DR PDBsum; 6N3N; -.
DR PDBsum; 6N3O; -.
DR PDBsum; 7E2K; -.
DR PDBsum; 7E2M; -.
DR PDBsum; 7QQ6; -.
DR AlphaFoldDB; Q9P2K8; -.
DR SMR; Q9P2K8; -.
DR BioGRID; 136426; 65.
DR IntAct; Q9P2K8; 32.
DR MINT; Q9P2K8; -.
DR STRING; 9606.ENSP00000263791; -.
DR BindingDB; Q9P2K8; -.
DR ChEMBL; CHEMBL5358; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9P2K8; -.
DR GuidetoPHARMACOLOGY; 2018; -.
DR iPTMnet; Q9P2K8; -.
DR PhosphoSitePlus; Q9P2K8; -.
DR BioMuta; EIF2AK4; -.
DR DMDM; 296439368; -.
DR EPD; Q9P2K8; -.
DR jPOST; Q9P2K8; -.
DR MassIVE; Q9P2K8; -.
DR MaxQB; Q9P2K8; -.
DR PaxDb; Q9P2K8; -.
DR PeptideAtlas; Q9P2K8; -.
DR PRIDE; Q9P2K8; -.
DR ProteomicsDB; 83838; -. [Q9P2K8-1]
DR ProteomicsDB; 83839; -. [Q9P2K8-2]
DR ProteomicsDB; 83840; -. [Q9P2K8-3]
DR Antibodypedia; 22934; 430 antibodies from 37 providers.
DR DNASU; 440275; -.
DR Ensembl; ENST00000263791.10; ENSP00000263791.5; ENSG00000128829.12. [Q9P2K8-1]
DR Ensembl; ENST00000559624.5; ENSP00000453148.1; ENSG00000128829.12. [Q9P2K8-3]
DR GeneID; 440275; -.
DR KEGG; hsa:440275; -.
DR MANE-Select; ENST00000263791.10; ENSP00000263791.5; NM_001013703.4; NP_001013725.2.
DR UCSC; uc001zkl.4; human. [Q9P2K8-1]
DR CTD; 440275; -.
DR DisGeNET; 440275; -.
DR GeneCards; EIF2AK4; -.
DR HGNC; HGNC:19687; EIF2AK4.
DR HPA; ENSG00000128829; Low tissue specificity.
DR MalaCards; EIF2AK4; -.
DR MIM; 234810; phenotype.
DR MIM; 609280; gene.
DR neXtProt; NX_Q9P2K8; -.
DR OpenTargets; ENSG00000128829; -.
DR Orphanet; 275777; Heritable pulmonary arterial hypertension.
DR Orphanet; 199241; Pulmonary capillary hemangiomatosis.
DR Orphanet; 31837; Pulmonary venoocclusive disease.
DR PharmGKB; PA134947616; -.
DR VEuPathDB; HostDB:ENSG00000128829; -.
DR eggNOG; KOG1035; Eukaryota.
DR GeneTree; ENSGT00940000156798; -.
DR HOGENOM; CLU_493107_0_0_1; -.
DR InParanoid; Q9P2K8; -.
DR OMA; GSEMIYE; -.
DR OrthoDB; 64059at2759; -.
DR PhylomeDB; Q9P2K8; -.
DR TreeFam; TF101512; -.
DR PathwayCommons; Q9P2K8; -.
DR Reactome; R-HSA-9633012; Response of EIF2AK4 (GCN2) to amino acid deficiency.
DR SignaLink; Q9P2K8; -.
DR SIGNOR; Q9P2K8; -.
DR BioGRID-ORCS; 440275; 64 hits in 1085 CRISPR screens.
DR ChiTaRS; EIF2AK4; human.
DR GeneWiki; EIF2AK4; -.
DR GenomeRNAi; 440275; -.
DR Pharos; Q9P2K8; Tchem.
DR PRO; PR:Q9P2K8; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q9P2K8; protein.
DR Bgee; ENSG00000128829; Expressed in adenohypophysis and 182 other tissues.
DR ExpressionAtlas; Q9P2K8; baseline and differential.
DR Genevisible; Q9P2K8; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0022626; C:cytosolic ribosome; ISS:UniProtKB.
DR GO; GO:0005844; C:polysome; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IMP: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; ISS:UniProtKB.
DR GO; GO:0000049; F:tRNA binding; ISS: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; IMP:UniProtKB.
DR GO; GO:0070417; P:cellular response to cold; IMP:UniProtKB.
DR GO; GO:1990253; P:cellular response to leucine starvation; ISS:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; ISS: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; IMP:UniProtKB.
DR GO; GO:0140469; P:GCN2-mediated signaling; IMP:UniProtKB.
DR GO; GO:0007612; P:learning; ISS:UniProtKB.
DR GO; GO:0007616; P:long-term memory; ISS:UniProtKB.
DR GO; GO:0044828; P:negative regulation by host of viral genome replication; ISS:UniProtKB.
DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISS:UniProtKB.
DR GO; GO:0045947; P:negative regulation of translational initiation; ISS:UniProtKB.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; ISS:UniProtKB.
DR GO; GO:1990138; P:neuron projection extension; ISS:UniProtKB.
DR GO; GO:0002821; P:positive regulation of adaptive immune response; ISS:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; ISS:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0071264; P:positive regulation of translational initiation in response to starvation; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0032268; P:regulation of cellular protein metabolic process; IEA:UniProt.
DR GO; GO:0060259; P:regulation of feeding behavior; ISS: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; IMP:UniProtKB.
DR GO; GO:0002286; P:T cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0019081; P:viral translation; ISS: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; Disease variant;
KW Growth arrest; Host-virus interaction; Immunity; Kinase; Neurogenesis;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat;
KW RNA-binding; Serine/threonine-protein kinase; Stress response; Transferase;
KW Translation regulation; tRNA-binding.
FT CHAIN 1..1649
FT /note="eIF-2-alpha kinase GCN2"
FT /id="PRO_0000085947"
FT DOMAIN 25..137
FT /note="RWD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00179"
FT DOMAIN 296..539
FT /note="Protein kinase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 590..1001
FT /note="Protein kinase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..25
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 138..158
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 227..256
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 660..750
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 765..788
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1022..1493
FT /note="Histidyl-tRNA synthetase-like"
FT COILED 146..205
FT /evidence="ECO:0000255"
FT COMPBIAS 140..158
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 706..720
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 765..783
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 848
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 596..604
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 619
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:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 667
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 871
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 899
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9QZ05"
FT MOD_RES 904
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 1259
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 608..616
FT /note="QNKLDGCCY -> WYRVIPSPL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_039185"
FT VAR_SEQ 617..1649
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_039186"
FT VAR_SEQ 774..801
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_013038"
FT VARIANT 137
FT /note="H -> R (in dbSNP:rs35509999)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040479"
FT VARIANT 166
FT /note="R -> W (in dbSNP:rs34439704)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040480"
FT VARIANT 441
FT /note="I -> L (in dbSNP:rs2291627)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:17974005"
FT /id="VAR_040481"
FT VARIANT 585
FT /note="R -> Q (in PVOD2; dbSNP:rs587777106)"
FT /evidence="ECO:0000269|PubMed:24292273"
FT /id="VAR_070990"
FT VARIANT 643
FT /note="L -> R (in PVOD2; dbSNP:rs757852728)"
FT /evidence="ECO:0000269|PubMed:24292273"
FT /id="VAR_070991"
FT VARIANT 872
FT /note="D -> V (in dbSNP:rs34665481)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040482"
FT VARIANT 939
FT /note="H -> Y (in a lung neuroendocrine carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040483"
FT VARIANT 1060
FT /note="T -> R (in dbSNP:rs55781333)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040484"
FT VARIANT 1306
FT /note="G -> C (in dbSNP:rs35602605)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_040485"
FT VARIANT 1336
FT /note="K -> R (in dbSNP:rs35480871)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040486"
FT VARIANT 1406
FT /note="Q -> H (in dbSNP:rs55721315)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040487"
FT CONFLICT 556
FT /note="E -> G (in Ref. 3; BAA92576 and 4; CAH10626)"
FT /evidence="ECO:0000305"
FT CONFLICT 629
FT /note="Q -> K (in Ref. 4; CAH10626)"
FT /evidence="ECO:0000305"
FT CONFLICT 858
FT /note="S -> F (in Ref. 5; BAB15625)"
FT /evidence="ECO:0000305"
FT CONFLICT 1133
FT /note="N -> I (in Ref. 6; CAB58360)"
FT /evidence="ECO:0000305"
FT HELIX 19..34
FT /evidence="ECO:0007829|PDB:7E2K"
FT HELIX 35..37
FT /evidence="ECO:0007829|PDB:7E2K"
FT STRAND 38..40
FT /evidence="ECO:0007829|PDB:7E2K"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:7E2K"
FT STRAND 54..59
FT /evidence="ECO:0007829|PDB:7E2K"
FT STRAND 66..69
FT /evidence="ECO:0007829|PDB:7E2M"
FT STRAND 70..78
FT /evidence="ECO:0007829|PDB:7E2K"
FT TURN 81..84
FT /evidence="ECO:0007829|PDB:7E2K"
FT STRAND 89..97
FT /evidence="ECO:0007829|PDB:7E2K"
FT HELIX 100..116
FT /evidence="ECO:0007829|PDB:7E2K"
FT TURN 117..119
FT /evidence="ECO:0007829|PDB:7E2K"
FT HELIX 123..136
FT /evidence="ECO:0007829|PDB:7E2K"
FT HELIX 585..589
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 590..599
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 602..609
FT /evidence="ECO:0007829|PDB:6N3O"
FT TURN 610..612
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 615..622
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 628..640
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 651..657
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 797..803
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 810..815
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 818..820
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 822..841
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 851..853
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 854..856
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 862..864
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 905..907
FT /evidence="ECO:0007829|PDB:6N3L"
FT HELIX 924..937
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 944..954
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 957..959
FT /evidence="ECO:0007829|PDB:6N3O"
FT TURN 964..966
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 967..969
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 972..981
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 986..988
FT /evidence="ECO:0007829|PDB:6N3O"
FT HELIX 992..997
FT /evidence="ECO:0007829|PDB:6N3O"
FT STRAND 998..1000
FT /evidence="ECO:0007829|PDB:6N3N"
SQ SEQUENCE 1649 AA; 186911 MW; ECF3CFFA51AEE67C CRC64;
MAGGRGAPGR GRDEPPESYP QRQDHELQAL EAIYGADFQD LRPDACGPVK EPPEINLVLY
PQGLTGEEVY VKVDLRVKCP PTYPDVVPEI ELKNAKGLSN ESVNLLKSRL EELAKKHCGE
VMIFELAYHV QSFLSEHNKP PPKSFHEEML ERRAQEEQQR LLEAKRKEEQ EQREILHEIQ
RRKEEIKEEK KRKEMAKQER LEIASLSNQD HTSKKDPGGH RTAAILHGGS PDFVGNGKHR
ANSSGRSRRE RQYSVCNSED SPGSCEILYF NMGSPDQLMV HKGKCIGSDE QLGKLVYNAL
ETATGGFVLL YEWVLQWQKK MGPFLTSQEK EKIDKCKKQI QGTETEFNSL VKLSHPNVVR
YLAMNLKEQD DSIVVDILVE HISGVSLAAH LSHSGPIPVH QLRRYTAQLL SGLDYLHSNS
VVHKVLSASN VLVDAEGTVK ITDYSISKRL ADICKEDVFE QTRVRFSDNA LPYKTGKKGD
VWRLGLLLLS LSQGQECGEY PVTIPSDLPA DFQDFLKKCV CLDDKERWSP QQLLKHSFIN
PQPKMPLVEQ SPEDSEGQDY VETVIPSNRL PSAAFFSETQ RQFSRYFIEF EELQLLGKGA
FGAVIKVQNK LDGCCYAVKR IPINPASRQF RRIKGEVTLL SRLHHENIVR YYNAWIERHE
RPAGPGTPPP DSGPLAKDDR AARGQPASDT DGLDSVEAAA PPPILSSSVE WSTSGERSAS
ARFPATGPGS SDDEDDDEDE HGGVFSQSFL PASDSESDII FDNEDENSKS QNQDEDCNEK
NGCHESEPSV TTEAVHYLYI QMEYCEKSTL RDTIDQGLYR DTVRLWRLFR EILDGLAYIH
EKGMIHRDLK PVNIFLDSDD HVKIGDFGLA TDHLAFSADS KQDDQTGDLI KSDPSGHLTG
MVGTALYVSP EVQGSTKSAY NQKVDLFSLG IIFFEMSYHP MVTASERIFV LNQLRDPTSP
KFPEDFDDGE HAKQKSVISW LLNHDPAKRP TATELLKSEL LPPPQMEESE LHEVLHHTLT
NVDGKAYRTM MAQIFSQRIS PAIDYTYDSD ILKGNFSIRT AKMQQHVCET IIRIFKRHGA
VQLCTPLLLP RNRQIYEHNE AALFMDHSGM LVMLPFDLRI PFARYVARNN ILNLKRYCIE
RVFRPRKLDR FHPKELLECA FDIVTSTTNS FLPTAEIIYT IYEIIQEFPA LQERNYSIYL
NHTMLLKAIL LHCGIPEDKL SQVYIILYDA VTEKLTRREV EAKFCNLSLS SNSLCRLYKF
IEQKGDLQDL MPTINSLIKQ KTGIAQLVKY GLKDLEEVVG LLKKLGIKLQ VLINLGLVYK
VQQHNGIIFQ FVAFIKRRQR AVPEILAAGG RYDLLIPQFR GPQALGPVPT AIGVSIAIDK
ISAAVLNMEE SVTISSCDLL VVSVGQMSMS RAINLTQKLW TAGITAEIMY DWSQSQEELQ
EYCRHHEITY VALVSDKEGS HVKVKSFEKE RQTEKRVLET ELVDHVLQKL RTKVTDERNG
REASDNLAVQ NLKGSFSNAS GLFEIHGATV VPIVSVLAPE KLSASTRRRY ETQVQTRLQT
SLANLHQKSS EIEILAVDLP KETILQFLSL EWDADEQAFN TTVKQLLSRL PKQRYLKLVC
DEIYNIKVEK KVSVLFLYSY RDDYYRILF
