E2AK3_HUMAN
ID E2AK3_HUMAN Reviewed; 1116 AA.
AC Q9NZJ5; A0AVH1; A0AVH2; B2RCU9; O95846; Q53QY0; Q53SB1;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 03-AUG-2022, entry version 206.
DE RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 3;
DE EC=2.7.11.1;
DE AltName: Full=PRKR-like endoplasmic reticulum kinase;
DE AltName: Full=Pancreatic eIF2-alpha kinase;
DE Short=HsPEK;
DE Flags: Precursor;
GN Name=EIF2AK3; Synonyms=PEK, PERK;
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 [MRNA], CHARACTERIZATION, AND VARIANTS ARG-166 AND
RP SER-704.
RC TISSUE=Liver, Pancreas, and Testis;
RX PubMed=10026192; DOI=10.1074/jbc.274.9.5723;
RA Shi Y., An J., Liang J., Hayes S.E., Sandusky G.E., Stramm L.E., Yang N.N.;
RT "Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-
RT localization with somatostatin in islet delta cells.";
RL J. Biol. Chem. 274:5723-5730(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, AND VARIANTS ARG-166 AND
RP SER-704.
RC TISSUE=Brain, and Pancreas;
RX PubMed=10677345; DOI=10.1042/bj3460281;
RA Sood R., Porter A.C., Ma K., Quilliam L.A., Wek R.C.;
RT "Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in
RT humans, Drosophila melanogaster and Caenorhabditis elegans that mediate
RT translational control in response to endoplasmic reticulum stress.";
RL Biochem. J. 346:281-293(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT WRS GLN-588, AND VARIANT
RP CYS-136.
RX PubMed=10932183; DOI=10.1038/78085;
RA Delepine M., Nicolino M., Barrett T., Golamaully M., Lathrop G.M.,
RA Julier C.;
RT "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is
RT mutated in patients with Wolcott-Rallison syndrome.";
RL Nat. Genet. 25:406-409(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-166 AND SER-704.
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 [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-715, AND IDENTIFICATION BY
RP 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 [8]
RP PHOSPHORYLATION AT TYR-619, AND DEPHOSPHORYLATION AT TYR-619.
RX PubMed=22169477; DOI=10.1126/scisignal.2002329;
RA Krishnan N., Fu C., Pappin D.J., Tonks N.K.;
RT "H2s-induced sulfhydration of the phosphatase PTP1B and its role in the
RT endoplasmic reticulum stress response.";
RL Sci. Signal. 4:RA86-RA86(2011).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1094, 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 [10]
RP ADP-RIBOSYLATION BY PARP16.
RX PubMed=23103912; DOI=10.1038/ncb2593;
RA Jwa M., Chang P.;
RT "PARP16 is a tail-anchored endoplasmic reticulum protein required for the
RT PERK-and IRE1alpha-mediated unfolded protein response.";
RL Nat. Cell Biol. 14:1223-1230(2012).
RN [11]
RP INTERACTION WITH PDIA6.
RX PubMed=24508390; DOI=10.1016/j.molcel.2014.01.004;
RA Eletto D., Eletto D., Dersh D., Gidalevitz T., Argon Y.;
RT "Protein disulfide isomerase A6 controls the decay of IRE1alpha signaling
RT via disulfide-dependent association.";
RL Mol. Cell 53:562-576(2014).
RN [12]
RP INTERACTION WITH TMEM33.
RX PubMed=26268696; DOI=10.1007/s10549-015-3536-7;
RA Sakabe I., Hu R., Jin L., Clarke R., Kasid U.N.;
RT "TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein
RT and modulator of the unfolded protein response signaling.";
RL Breast Cancer Res. Treat. 153:285-297(2015).
RN [13]
RP INTERACTION WITH LACC1.
RX PubMed=31875558; DOI=10.1016/j.celrep.2019.11.105;
RA Huang C., Hedl M., Ranjan K., Abraham C.;
RT "LACC1 required for NOD2-induced, ER stress-mediated innate immune outcomes
RT in human macrophages and LACC1 risk variants modulate these outcomes.";
RL Cell Rep. 29:4525-4539(2019).
RN [14]
RP FUNCTION.
RX PubMed=33384352; DOI=10.1126/science.abb6896;
RA You K., Wang L., Chou C.H., Liu K., Nakata T., Jaiswal A., Yao J.,
RA Lefkovith A., Omar A., Perrigoue J.G., Towne J.E., Regev A., Graham D.B.,
RA Xavier R.J.;
RT "QRICH1 dictates the outcome of ER stress through transcriptional control
RT of proteostasis.";
RL Science 371:0-0(2021).
RN [15]
RP VARIANTS [LARGE SCALE ANALYSIS] CYS-136; VAL-566 AND LEU-716.
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 various stress conditions. Key
CC activator of the integrated stress response (ISR) required for
CC adaptation to various stress, such as unfolded protein response (UPR)
CC and low amino acid availability (By similarity). EIF2S1/eIF-2-alpha
CC phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a
CC global protein synthesis inhibitor, leading to a global attenuation of
CC cap-dependent translation, while concomitantly initiating the
CC preferential translation of ISR-specific mRNAs, such as the
CC transcriptional activators ATF4 and QRICH1, and hence allowing
CC ATF4- and QRICH1-mediated reprogramming (PubMed:33384352). Serves as a
CC critical effector of unfolded protein response (UPR)-induced G1 growth
CC arrest due to the loss of cyclin-D1 (CCND1). Involved in control of
CC mitochondrial morphology and function (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:33384352}.
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 -!- 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;
CC -!- ACTIVITY REGULATION: Perturbation in protein folding in the endoplasmic
CC reticulum (ER) promotes reversible dissociation from HSPA5/BIP and
CC oligomerization, resulting in transautophosphorylation and kinase
CC activity induction. {ECO:0000250|UniProtKB:Q9Z2B5}.
CC -!- SUBUNIT: Forms dimers with HSPA5/BIP in resting cells (By similarity).
CC Oligomerizes in ER-stressed cells (By similarity). Interacts with
CC DNAJC3 and MFN2 (By similarity). Interacts with TMEM33
CC (PubMed:26268696). Interacts with PDIA6 (PubMed:24508390). Interacts
CC with LACC1 (PubMed:31875558). {ECO:0000250|UniProtKB:Q9Z2B5,
CC ECO:0000269|PubMed:24508390, ECO:0000269|PubMed:26268696,
CC ECO:0000269|PubMed:31875558}.
CC -!- INTERACTION:
CC Q9NZJ5; Q9NZJ5: EIF2AK3; NbExp=2; IntAct=EBI-766076, EBI-766076;
CC Q9NZJ5; P11021: HSPA5; NbExp=4; IntAct=EBI-766076, EBI-354921;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass type
CC I membrane protein.
CC -!- TISSUE SPECIFICITY: Ubiquitous. A high level expression is seen in
CC secretory tissues.
CC -!- INDUCTION: By endoplasmic reticulum stress.
CC -!- DOMAIN: The lumenal domain senses perturbations in protein folding in
CC the ER, probably through reversible interaction with HSPA5/BIP.
CC {ECO:0000250}.
CC -!- PTM: Oligomerization of the N-terminal ER luminal domain by ER stress
CC promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic
CC kinase domain at multiple residues including Thr-982 on the kinase
CC activation loop (By similarity). Autophosphorylated. Phosphorylated at
CC Tyr-619 following endoplasmic reticulum stress, leading to activate its
CC tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B,
CC leading to inactivate its enzyme activity. {ECO:0000250,
CC ECO:0000269|PubMed:22169477}.
CC -!- PTM: N-glycosylated. {ECO:0000250}.
CC -!- PTM: ADP-ribosylated by PARP16 upon ER stress, which increases kinase
CC activity.
CC -!- DISEASE: Wolcott-Rallison syndrome (WRS) [MIM:226980]: A rare autosomal
CC recessive disorder, characterized by permanent neonatal or early
CC infancy insulin-dependent diabetes and, at a later age, epiphyseal
CC dysplasia, osteoporosis, growth retardation and other multisystem
CC manifestations, such as hepatic and renal dysfunctions, intellectual
CC disability and cardiovascular abnormalities.
CC {ECO:0000269|PubMed:10932183}. 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}.
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DR EMBL; AF110146; AAD19961.1; -; mRNA.
DR EMBL; AF193339; AAF61199.1; -; mRNA.
DR EMBL; AF284615; AAF91480.1; -; Genomic_DNA.
DR EMBL; AF284604; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284605; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284606; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284607; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284608; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284609; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284610; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284611; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284612; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284613; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AF284614; AAF91480.1; JOINED; Genomic_DNA.
DR EMBL; AK315287; BAG37696.1; -; mRNA.
DR EMBL; AC062029; AAY14777.1; -; Genomic_DNA.
DR EMBL; AC104134; AAY24331.1; -; Genomic_DNA.
DR EMBL; BC126354; AAI26355.1; -; mRNA.
DR EMBL; BC126356; AAI26357.1; -; mRNA.
DR CCDS; CCDS33241.1; -.
DR RefSeq; NP_004827.4; NM_004836.6.
DR PDB; 4G31; X-ray; 2.28 A; A=588-1093.
DR PDB; 4G34; X-ray; 2.70 A; A=588-1093.
DR PDB; 4M7I; X-ray; 2.34 A; A=588-1093.
DR PDB; 4X7H; X-ray; 2.00 A; A=575-1094.
DR PDB; 4X7J; X-ray; 2.30 A; A=575-1094.
DR PDB; 4X7K; X-ray; 1.80 A; A=575-1094.
DR PDB; 4X7L; X-ray; 1.90 A; A=575-1094.
DR PDB; 4X7N; X-ray; 2.35 A; A=575-1094.
DR PDB; 4X7O; X-ray; 2.65 A; A=575-1094.
DR PDB; 4YZS; X-ray; 3.14 A; A/B=104-403.
DR PDB; 5SV7; X-ray; 3.21 A; A/B/C/D=95-420.
DR PDB; 7MF0; X-ray; 2.81 A; AAA=575-1094.
DR PDBsum; 4G31; -.
DR PDBsum; 4G34; -.
DR PDBsum; 4M7I; -.
DR PDBsum; 4X7H; -.
DR PDBsum; 4X7J; -.
DR PDBsum; 4X7K; -.
DR PDBsum; 4X7L; -.
DR PDBsum; 4X7N; -.
DR PDBsum; 4X7O; -.
DR PDBsum; 4YZS; -.
DR PDBsum; 5SV7; -.
DR PDBsum; 7MF0; -.
DR AlphaFoldDB; Q9NZJ5; -.
DR SMR; Q9NZJ5; -.
DR BioGRID; 114840; 152.
DR IntAct; Q9NZJ5; 41.
DR MINT; Q9NZJ5; -.
DR STRING; 9606.ENSP00000307235; -.
DR BindingDB; Q9NZJ5; -.
DR ChEMBL; CHEMBL6030; -.
DR GuidetoPHARMACOLOGY; 2017; -.
DR GlyGen; Q9NZJ5; 2 sites.
DR iPTMnet; Q9NZJ5; -.
DR PhosphoSitePlus; Q9NZJ5; -.
DR BioMuta; EIF2AK3; -.
DR DMDM; 296439367; -.
DR EPD; Q9NZJ5; -.
DR jPOST; Q9NZJ5; -.
DR MassIVE; Q9NZJ5; -.
DR MaxQB; Q9NZJ5; -.
DR PaxDb; Q9NZJ5; -.
DR PeptideAtlas; Q9NZJ5; -.
DR PRIDE; Q9NZJ5; -.
DR ProteomicsDB; 83416; -.
DR Antibodypedia; 2635; 648 antibodies from 39 providers.
DR DNASU; 9451; -.
DR Ensembl; ENST00000303236.9; ENSP00000307235.3; ENSG00000172071.15.
DR GeneID; 9451; -.
DR KEGG; hsa:9451; -.
DR MANE-Select; ENST00000303236.9; ENSP00000307235.3; NM_004836.7; NP_004827.4.
DR UCSC; uc002stc.5; human.
DR CTD; 9451; -.
DR DisGeNET; 9451; -.
DR GeneCards; EIF2AK3; -.
DR HGNC; HGNC:3255; EIF2AK3.
DR HPA; ENSG00000172071; Tissue enhanced (pancreas).
DR MalaCards; EIF2AK3; -.
DR MIM; 226980; phenotype.
DR MIM; 604032; gene.
DR neXtProt; NX_Q9NZJ5; -.
DR OpenTargets; ENSG00000172071; -.
DR Orphanet; 1667; Wolcott-Rallison syndrome.
DR PharmGKB; PA27687; -.
DR VEuPathDB; HostDB:ENSG00000172071; -.
DR eggNOG; KOG1033; Eukaryota.
DR GeneTree; ENSGT00940000158121; -.
DR InParanoid; Q9NZJ5; -.
DR OMA; QCQTDCK; -.
DR OrthoDB; 1610714at2759; -.
DR PhylomeDB; Q9NZJ5; -.
DR TreeFam; TF101511; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; Q9NZJ5; -.
DR Reactome; R-HSA-381042; PERK regulates gene expression.
DR Reactome; R-HSA-9700645; ALK mutants bind TKIs.
DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants.
DR SignaLink; Q9NZJ5; -.
DR SIGNOR; Q9NZJ5; -.
DR BioGRID-ORCS; 9451; 21 hits in 1111 CRISPR screens.
DR ChiTaRS; EIF2AK3; human.
DR GeneWiki; EIF2AK3; -.
DR GenomeRNAi; 9451; -.
DR Pharos; Q9NZJ5; Tchem.
DR PRO; PR:Q9NZJ5; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9NZJ5; protein.
DR Bgee; ENSG00000172071; Expressed in body of pancreas and 197 other tissues.
DR ExpressionAtlas; Q9NZJ5; baseline and differential.
DR Genevisible; Q9NZJ5; HS.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; NAS:ParkinsonsUK-UCL.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0019903; F:protein phosphatase binding; IPI:UniProtKB.
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:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0030282; P:bone mineralization; ISS:UniProtKB.
DR GO; GO:0019722; P:calcium-mediated signaling; ISS:UniProtKB.
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:0042149; P:cellular response to glucose starvation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0002063; P:chondrocyte development; ISS:UniProtKB.
DR GO; GO:0036492; P:eiF2alpha phosphorylation in response to endoplasmic reticulum stress; IMP:UniProtKB.
DR GO; GO:0031018; P:endocrine pancreas development; IMP:UniProtKB.
DR GO; GO:0007029; P:endoplasmic reticulum organization; ISS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:UniProtKB.
DR GO; GO:0006983; P:ER overload response; IDA:UniProtKB.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0031642; P:negative regulation of myelination; ISS:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; TAS:UniProtKB.
DR GO; GO:0032055; P:negative regulation of translation in response to stress; IEA:Ensembl.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; TAS:UniProtKB.
DR GO; GO:0001503; P:ossification; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:ParkinsonsUK-UCL.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; TAS:ParkinsonsUK-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; ISS:ParkinsonsUK-UCL.
DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:ParkinsonsUK-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0060734; P:regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation; ISS:UniProtKB.
DR GO; GO:1902235; P:regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010998; P:regulation of translational initiation by eIF2 alpha phosphorylation; ISS:ParkinsonsUK-UCL.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:BHF-UCL.
DR GO; GO:1990737; P:response to manganese-induced endoplasmic reticulum stress; IEA:Ensembl.
DR GO; GO:0001501; P:skeletal system development; ISS:UniProtKB.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR011047; Quinoprotein_ADH-like_supfam.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR Pfam; PF00069; Pkinase; 2.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF50998; SSF50998; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ADP-ribosylation; ATP-binding; Diabetes mellitus;
KW Disease variant; Endoplasmic reticulum; Glycoprotein; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Signal; Stress response; Transferase;
KW Translation regulation; Transmembrane; Transmembrane helix;
KW Unfolded protein response.
FT SIGNAL 1..29
FT /evidence="ECO:0000255"
FT CHAIN 30..1116
FT /note="Eukaryotic translation initiation factor 2-alpha
FT kinase 3"
FT /id="PRO_0000024322"
FT TOPO_DOM 30..514
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 515..535
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 536..1116
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 593..1077
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 77..101
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 550..571
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 841..863
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1090..1116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 87..101
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 937
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 599..607
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 622
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 619
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:22169477"
FT MOD_RES 715
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 982
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2B5"
FT MOD_RES 1094
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 136
FT /note="S -> C (in dbSNP:rs867529)"
FT /evidence="ECO:0000269|PubMed:10932183,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_011409"
FT VARIANT 166
FT /note="Q -> R (in dbSNP:rs13045)"
FT /evidence="ECO:0000269|PubMed:10026192,
FT ECO:0000269|PubMed:10677345, ECO:0000269|PubMed:15489334"
FT /id="VAR_011410"
FT VARIANT 566
FT /note="D -> V (in dbSNP:rs55791823)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040477"
FT VARIANT 588
FT /note="R -> Q (in WRS; dbSNP:rs121908569)"
FT /evidence="ECO:0000269|PubMed:10932183"
FT /id="VAR_011408"
FT VARIANT 704
FT /note="A -> S (in dbSNP:rs1805165)"
FT /evidence="ECO:0000269|PubMed:10026192,
FT ECO:0000269|PubMed:10677345, ECO:0000269|PubMed:15489334"
FT /id="VAR_011411"
FT VARIANT 716
FT /note="P -> L (in dbSNP:rs55861585)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040478"
FT CONFLICT 14
FT /note="Missing (in Ref. 1; AAD19961, 2; AAF61199, 3;
FT AAF91480, 4; BAG37696 and 6; AAI26357)"
FT /evidence="ECO:0000305"
FT CONFLICT 490
FT /note="N -> H (in Ref. 2; AAF61199)"
FT /evidence="ECO:0000305"
FT STRAND 105..110
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 113..118
FT /evidence="ECO:0007829|PDB:4YZS"
FT TURN 120..123
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 126..131
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 137..139
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 152..158
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 161..164
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 166..169
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:4YZS"
FT HELIX 178..182
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 193..204
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 207..209
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 215..217
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 237..248
FT /evidence="ECO:0007829|PDB:4YZS"
FT TURN 250..252
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 255..267
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 308..310
FT /evidence="ECO:0007829|PDB:4YZS"
FT TURN 314..317
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 321..323
FT /evidence="ECO:0007829|PDB:4YZS"
FT TURN 324..326
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 339..346
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 349..352
FT /evidence="ECO:0007829|PDB:4YZS"
FT HELIX 375..383
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 387..390
FT /evidence="ECO:0007829|PDB:4YZS"
FT STRAND 392..398
FT /evidence="ECO:0007829|PDB:4YZS"
FT HELIX 588..592
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 593..602
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 605..612
FT /evidence="ECO:0007829|PDB:4X7K"
FT TURN 613..615
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 618..625
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 630..644
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 654..660
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 883..889
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 896..901
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 906..908
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 911..930
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 940..942
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 943..945
FT /evidence="ECO:0007829|PDB:4X7K"
FT STRAND 951..953
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 993..996
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1004..1018
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1024..1035
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1041..1046
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1048..1057
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1062..1064
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1068..1072
FT /evidence="ECO:0007829|PDB:4X7K"
FT HELIX 1075..1077
FT /evidence="ECO:0007829|PDB:4X7K"
SQ SEQUENCE 1116 AA; 125216 MW; 95FEB5DAE8D3D452 CRC64;
MERAISPGLL VRALLLLLLL LGLAARTVAA GRARGLPAPT AEAAFGLGAA AAPTSATRVP
AAGAVAAAEV TVEDAEALPA AAGEQEPRGP EPDDETELRP RGRSLVIIST LDGRIAALDP
ENHGKKQWDL DVGSGSLVSS SLSKPEVFGN KMIIPSLDGA LFQWDQDRES METVPFTVES
LLESSYKFGD DVVLVGGKSL TTYGLSAYSG KVRYICSALG CRQWDSDEME QEEDILLLQR
TQKTVRAVGP RSGNEKWNFS VGHFELRYIP DMETRAGFIE STFKPNENTE ESKIISDVEE
QEAAIMDIVI KVSVADWKVM AFSKKGGHLE WEYQFCTPIA SAWLLKDGKV IPISLFDDTS
YTSNDDVLED EEDIVEAARG ATENSVYLGM YRGQLYLQSS VRISEKFPSS PKALESVTNE
NAIIPLPTIK WKPLIHSPSR TPVLVGSDEF DKCLSNDKFS HEEYSNGALS ILQYPYDNGY
YLPYYKRERN KRSTQITVRF LDNPHYNKNI RKKDPVLLLH WWKEIVATIL FCIIATTFIV
RRLFHPHPHR QRKESETQCQ TENKYDSVSG EANDSSWNDI KNSGYISRYL TDFEPIQCLG
RGGFGVVFEA KNKVDDCNYA IKRIRLPNRE LAREKVMREV KALAKLEHPG IVRYFNAWLE
APPEKWQEKM DEIWLKDEST DWPLSSPSPM DAPSVKIRRM DPFATKEHIE IIAPSPQRSR
SFSVGISCDQ TSSSESQFSP LEFSGMDHED ISESVDAAYN LQDSCLTDCD VEDGTMDGND
EGHSFELCPS EASPYVRSRE RTSSSIVFED SGCDNASSKE EPKTNRLHIG NHCANKLTAF
KPTSSKSSSE ATLSISPPRP TTLSLDLTKN TTEKLQPSSP KVYLYIQMQL CRKENLKDWM
NGRCTIEERE RSVCLHIFLQ IAEAVEFLHS KGLMHRDLKP SNIFFTMDDV VKVGDFGLVT
AMDQDEEEQT VLTPMPAYAR HTGQVGTKLY MSPEQIHGNS YSHKVDIFSL GLILFELLYP
FSTQMERVRT LTDVRNLKFP PLFTQKYPCE YVMVQDMLSP SPMERPEAIN IIENAVFEDL
DFPGKTVLRQ RSRSLSSSGT KHSRQSNNSH SPLPSN
