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E2AK3_RAT
ID   E2AK3_RAT               Reviewed;        1108 AA.
AC   Q9Z1Z1;
DT   26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   03-AUG-2022, entry version 174.
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   Flags: Precursor;
GN   Name=Eif2ak3; Synonyms=Pek, Perk;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND CHARACTERIZATION.
RC   TISSUE=Pancreatic islet;
RX   PubMed=9819435; DOI=10.1128/mcb.18.12.7499;
RA   Shi Y., Vattem K.M., Sood R., An J., Liang J., Stramm L.E., Wek R.C.;
RT   "Identification and characterization of pancreatic eukaryotic initiation
RT   factor 2 alpha-subunit kinase, PEK, involved in translational control.";
RL   Mol. Cell. Biol. 18:7499-7509(1998).
RN   [2]
RP   MUTAGENESIS OF LYS-614.
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   [3]
RP   SUBUNIT.
RX   PubMed=10854322; DOI=10.1038/35014014;
RA   Bertolotti A., Zhang Y., Hendershot L.M., Harding H.P., Ron D.;
RT   "Dynamic interaction of BiP and ER stress transducers in the unfolded-
RT   protein response.";
RL   Nat. Cell Biol. 2:326-332(2000).
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 (By similarity). 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:Q9NZJ5, ECO:0000250|UniProtKB:Q9Z2B5}.
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: Interacts with DNAJC3 and MFN2 (By similarity). Forms dimers
CC       with HSPA5/BIP in resting cells (By similarity). Oligomerizes in ER-
CC       stressed cells (PubMed:10854322). Interacts with TMEM33 (By
CC       similarity). Interacts with PDIA6 (By similarity). Interacts with LACC1
CC       (By similarity). {ECO:0000250|UniProtKB:Q9NZJ5,
CC       ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:10854322}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass type
CC       I membrane protein.
CC   -!- TISSUE SPECIFICITY: Ubiquitous.
CC   -!- INDUCTION: By ER stress.
CC   -!- DOMAIN: The lumenal domain senses perturbations in protein folding in
CC       the ER, probably through reversible interaction with HSPA5/BIP.
CC   -!- PTM: Autophosphorylated. Phosphorylated at Tyr-611 following
CC       endoplasmic reticulum stress, leading to activate its tyrosine-protein
CC       kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate
CC       its enzyme activity (By similarity). {ECO:0000250}.
CC   -!- PTM: N-glycosylated. {ECO:0000250}.
CC   -!- PTM: ADP-ribosylated by PARP16 upon ER stress, which increases kinase
CC       activity. {ECO:0000250}.
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; AF096835; AAC83801.1; -; mRNA.
DR   PIR; T17455; T17455.
DR   RefSeq; NP_113787.1; NM_031599.2.
DR   AlphaFoldDB; Q9Z1Z1; -.
DR   SMR; Q9Z1Z1; -.
DR   BioGRID; 248320; 1.
DR   STRING; 10116.ENSRNOP00000008451; -.
DR   BindingDB; Q9Z1Z1; -.
DR   ChEMBL; CHEMBL4105946; -.
DR   GlyGen; Q9Z1Z1; 1 site.
DR   iPTMnet; Q9Z1Z1; -.
DR   PhosphoSitePlus; Q9Z1Z1; -.
DR   PaxDb; Q9Z1Z1; -.
DR   PRIDE; Q9Z1Z1; -.
DR   Ensembl; ENSRNOT00000008451; ENSRNOP00000008451; ENSRNOG00000006069.
DR   GeneID; 29702; -.
DR   KEGG; rno:29702; -.
DR   UCSC; RGD:70884; rat.
DR   CTD; 9451; -.
DR   RGD; 70884; Eif2ak3.
DR   eggNOG; KOG1033; Eukaryota.
DR   GeneTree; ENSGT00940000158121; -.
DR   HOGENOM; CLU_009091_0_0_1; -.
DR   InParanoid; Q9Z1Z1; -.
DR   OMA; QCQTDCK; -.
DR   OrthoDB; 64059at2759; -.
DR   PhylomeDB; Q9Z1Z1; -.
DR   TreeFam; TF101511; -.
DR   Reactome; R-RNO-381042; PERK regulates gene expression.
DR   PRO; PR:Q9Z1Z1; -.
DR   Proteomes; UP000002494; Chromosome 4.
DR   Bgee; ENSRNOG00000006069; Expressed in pancreas and 20 other tissues.
DR   Genevisible; Q9Z1Z1; RN.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; ISO:RGD.
DR   GO; GO:0044322; C:endoplasmic reticulum quality control compartment; ISO:RGD.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR   GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:RGD.
DR   GO; GO:0051879; F:Hsp90 protein binding; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR   GO; GO:0019903; F:protein phosphatase binding; ISO:RGD.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:RGD.
DR   GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR   GO; GO:0001525; P:angiogenesis; ISO:RGD.
DR   GO; GO:0030282; P:bone mineralization; ISO:RGD.
DR   GO; GO:0019722; P:calcium-mediated signaling; ISO:RGD.
DR   GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR   GO; GO:0070417; P:cellular response to cold; ISS:UniProtKB.
DR   GO; GO:0042149; P:cellular response to glucose starvation; ISO:RGD.
DR   GO; GO:0002063; P:chondrocyte development; ISO:RGD.
DR   GO; GO:0036492; P:eiF2alpha phosphorylation in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR   GO; GO:0031018; P:endocrine pancreas development; ISS:UniProtKB.
DR   GO; GO:0007029; P:endoplasmic reticulum organization; ISO:RGD.
DR   GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISS:UniProtKB.
DR   GO; GO:0006983; P:ER overload response; ISS:UniProtKB.
DR   GO; GO:0045444; P:fat cell differentiation; ISO:RGD.
DR   GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISO:RGD.
DR   GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISO:RGD.
DR   GO; GO:0007595; P:lactation; ISO:RGD.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR   GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR   GO; GO:0031642; P:negative regulation of myelination; ISO:RGD.
DR   GO; GO:0017148; P:negative regulation of translation; ISO:RGD.
DR   GO; GO:1902010; P:negative regulation of translation in response to endoplasmic reticulum stress; ISO:RGD.
DR   GO; GO:0032055; P:negative regulation of translation in response to stress; IDA:RGD.
DR   GO; GO:0001503; P:ossification; ISS:UniProtKB.
DR   GO; GO:0031016; P:pancreas development; ISO:RGD.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:RGD.
DR   GO; GO:0036499; P:PERK-mediated unfolded protein response; ISO:RGD.
DR   GO; GO:1902237; P:positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; ISO:RGD.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR   GO; GO:1903788; P:positive regulation of glutathione biosynthetic process; ISO:RGD.
DR   GO; GO:0032092; P:positive regulation of protein binding; ISO:RGD.
DR   GO; GO:1900182; P:positive regulation of protein localization to nucleus; ISO:RGD.
DR   GO; GO:0009967; P:positive regulation of signal transduction; ISO:RGD.
DR   GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; ISO:RGD.
DR   GO; GO:1990440; P:positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; ISO:RGD.
DR   GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:RGD.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:RGD.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
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; ISO:RGD.
DR   GO; GO:0019217; P:regulation of fatty acid metabolic process; ISO:RGD.
DR   GO; GO:0010998; P:regulation of translational initiation by eIF2 alpha phosphorylation; ISO:RGD.
DR   GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR   GO; GO:1990737; P:response to manganese-induced endoplasmic reticulum stress; IEP:ParkinsonsUK-UCL.
DR   GO; GO:0001501; P:skeletal system development; ISO:RGD.
DR   GO; GO:0032933; P:SREBP signaling pathway; ISO:RGD.
DR   GO; GO:0006412; P:translation; ISO:RGD.
DR   GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; ISO:RGD.
DR   Gene3D; 2.130.10.10; -; 1.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
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; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   ADP-ribosylation; ATP-binding; Endoplasmic reticulum; Glycoprotein; Kinase;
KW   Membrane; 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..27
FT                   /evidence="ECO:0000255"
FT   CHAIN           28..1108
FT                   /note="Eukaryotic translation initiation factor 2-alpha
FT                   kinase 3"
FT                   /id="PRO_0000024324"
FT   TOPO_DOM        28..506
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        507..527
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        528..1108
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          585..1069
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          71..92
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          542..563
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          772..818
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          832..856
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1080..1108
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        787..804
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1081..1108
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        929
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         591..599
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         614
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   MOD_RES         611
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NZJ5"
FT   MOD_RES         707
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NZJ5"
FT   MOD_RES         974
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2B5"
FT   MOD_RES         1086
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NZJ5"
FT   CARBOHYD        253
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   MUTAGEN         614
FT                   /note="K->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:10026192"
SQ   SEQUENCE   1108 AA;  124770 MW;  B3716B1FD26ED32B CRC64;
     MERATQPRPR ALLLLFLLLG CAAGISAVAR ARSLLAPTSD TAFGLGAAAA PTSAARVPAV
     ATAEVTVEDA EALPAASGEQ ESRATESDDD VELRPRGRSL VIISTLDGRI AALDAENHGK
     KQWDLDVGSG SLVSSSLSKP EVFGNKMIIP SLDGDLFQWD RDRESMEAVP FTVESLLESS
     YKFGDDVVLV GGKSLTTYGL SAYSGKLRYI CSALGCRRWD SDEMEEEEDI LLLQRTQKTV
     RAVGPRSGSE KWNFSVGHFE LRYIPDMETR AGFIESTFKL GGNKEDSKII SDVEEQDVDT
     VIKVSVADWK VMAFSKKGGR LEWEYQFCTP IASAWLVRDG KVIPISLFDD TSYTANEEVL
     EDEEDIVEAA RGATENSVYL GMYRGQLYLQ SSVRVSEKFP TRPKALESVN GESAIIPLPT
     IKWKPLIHSP SRTPVLVGSD EFDKCLSNDK YSHEEYSNGA LSILQYPYDN GYYLPYYKRE
     RNKRSTQITV RFLDSPHYSK NIRKKDPILL LHWWKEIFGT ILLCIVATTF IVRRLFHPQP
     HRQRKESETQ CQTESKYDSV SADNSDNSWN DIKHSGYVSR YLTDFEPIQC MGRGGFGVVF
     EAKNKVDDCN YAIKRIRLPN RELAREKVMR EVKALAKLEH PGIVRYFNAW LETPPEKWQE
     EMDEIWLKDE STDWPLSSPS PMDAPSVKIR QMDPFSTKEQ IEVIAPSPER SRSFSVGISC
     GRTSSSESQF SPLEFSGTDC GDNSDSEDAA HNLQDSCLTD CDMEDGTVDG DDEGHSFELC
     PSEASPYTRS REGTSSSIVF EDSGCDNASS KEDPRMNRLH NGHHYVNKLT EFKHSSSRSS
     SEATLSTSPT RPTTLSLDFT RNTVDRLQPS SPKVYLYIQM QLCRKENLKD WMNRRCSMED
     REHRVCLHIF LQIAEAVQFL HSKGLMHRDL KPSNIFFTMD DVVKVGDFGL VTAMDQDEEE
     QTVLTPMPAY ATHTGQVGTK LYMSPEQIHG NNYSHKVDIF SLGLILFELL YPFSTQMERV
     RTLTDVRNLK FPPLFTQKYP QEHMMVQDML SPSPMERPEA TDIIENAVFE NLEFPGKTVL
     RQRSRSLSSS GTKHSRQPSS TFSPLPGN
 
 
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