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 27-MAR-2024, entry version 215. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 8EQ9; X-ray; 2.86 A; AAA=575-1094. DR PDB; 8EQD; X-ray; 2.92 A; AAA=575-1094. DR PDB; 8EQE; X-ray; 2.56 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 PDBsum; 8EQ9; -. DR PDBsum; 8EQD; -. DR PDBsum; 8EQE; -. DR AlphaFoldDB; Q9NZJ5; -. DR SMR; Q9NZJ5; -. DR BioGRID; 114840; 164. DR IntAct; Q9NZJ5; 41. DR MINT; Q9NZJ5; -. DR STRING; 9606.ENSP00000307235; -. DR BindingDB; Q9NZJ5; -. DR ChEMBL; CHEMBL6030; -. DR GuidetoPHARMACOLOGY; 2017; -. DR TCDB; 8.A.23.1.57; the basigin (basigin) family. DR GlyCosmos; Q9NZJ5; 1 site, No reported glycans. DR GlyGen; Q9NZJ5; 6 sites, 1 O-linked glycan (4 sites). DR iPTMnet; Q9NZJ5; -. DR PhosphoSitePlus; Q9NZJ5; -. DR SwissPalm; Q9NZJ5; -. DR BioMuta; EIF2AK3; -. DR DMDM; 296439367; -. DR EPD; Q9NZJ5; -. DR jPOST; Q9NZJ5; -. DR MassIVE; Q9NZJ5; -. DR MaxQB; Q9NZJ5; -. DR PaxDb; 9606-ENSP00000307235; -. DR PeptideAtlas; Q9NZJ5; -. DR ProteomicsDB; 83416; -. DR Pumba; Q9NZJ5; -. DR Antibodypedia; 2635; 735 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 AGR; HGNC:3255; -. 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; YEPTCGD; -. DR OrthoDB; 8734at2759; -. 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 Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR SignaLink; Q9NZJ5; -. DR SIGNOR; Q9NZJ5; -. DR BioGRID-ORCS; 9451; 22 hits in 1192 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 199 other cell types or tissues. DR ExpressionAtlas; Q9NZJ5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. 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; TAS:ProtInc. 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:0045947; P:negative regulation of translational initiation; TAS:BHF-UCL. 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 CDD; cd09768; Luminal_EIF2AK3; 1. DR CDD; cd14048; STKc_EIF2AK3_PERK; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 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 PANTHER; PTHR11042:SF166; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 3; 1. DR PANTHER; PTHR11042; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE EIF2-ALPHA KINASE -RELATED; 1. DR Pfam; PF00069; Pkinase; 2. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF50998; Quinoprotein alcohol dehydrogenase-like; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q9NZJ5; HS. 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 //