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Protein

Eukaryotic translation initiation factor 2-alpha kinase 3

Gene

Eif2ak3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' during the unfolded protein response (UPR) and in response to low amino acid availability. Converts phosphorylated eIF-2-alpha/EIF2S1 either in a global protein synthesis inhibitor, leading to a reduced overall utilization of amino acids, or to a translation initiation activator of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function.By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in transautophosphorylation and kinase activity induction.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei614 – 6141ATP
Active sitei929 – 9291Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi591 – 5999ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • eukaryotic translation initiation factor 2alpha kinase activity Source: UniProtKB
  • Hsp90 protein binding Source: ParkinsonsUK-UCL
  • protein serine/threonine kinase activity Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Stress response, Translation regulation, Unfolded protein response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-RNO-381042. PERK regulates gene expression.

Names & Taxonomyi

Protein namesi
Recommended name:
Eukaryotic translation initiation factor 2-alpha kinase 3 (EC:2.7.11.1)
Alternative name(s):
PRKR-like endoplasmic reticulum kinase
Pancreatic eIF2-alpha kinase
Gene namesi
Name:Eif2ak3
Synonyms:Pek, Perk
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 4

Organism-specific databases

RGDi70884. Eif2ak3.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini28 – 506479LumenalSequence analysisAdd
BLAST
Transmembranei507 – 52721HelicalSequence analysisAdd
BLAST
Topological domaini528 – 1108581CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi614 – 6141K → A: Loss of activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2727Sequence analysisAdd
BLAST
Chaini28 – 11081081Eukaryotic translation initiation factor 2-alpha kinase 3PRO_0000024324Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi253 – 2531N-linked (GlcNAc...)Sequence analysis
Modified residuei611 – 6111PhosphotyrosineBy similarity
Modified residuei707 – 7071PhosphoserineBy similarity
Modified residuei974 – 9741PhosphothreonineBy similarity
Modified residuei1086 – 10861PhosphoserineBy similarity

Post-translational modificationi

Autophosphorylated. Phosphorylated at Tyr-611 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity (By similarity).By similarity
N-glycosylated.By similarity
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.By similarity

Keywords - PTMi

ADP-ribosylation, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9Z1Z1.
PRIDEiQ9Z1Z1.

PTM databases

iPTMnetiQ9Z1Z1.
PhosphoSiteiQ9Z1Z1.

Expressioni

Tissue specificityi

Ubiquitous.

Inductioni

By ER stress.

Gene expression databases

BgeeiENSRNOG00000006069.
GenevisibleiQ9Z1Z1. RN.

Interactioni

Subunit structurei

Interacts with DNAJC3 and MFN2 (By similarity). Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with TMEM33 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • Hsp90 protein binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008451.

Structurei

3D structure databases

ProteinModelPortaliQ9Z1Z1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini585 – 1069485Protein kinasePROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi47 – 504Poly-Ala
Compositional biasi223 – 2286Poly-Glu

Domaini

The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1033. Eukaryota.
ENOG410XS0B. LUCA.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000112308.
HOVERGENiHBG051431.
InParanoidiQ9Z1Z1.
KOiK08860.
OMAiKWKPLIH.
OrthoDBiEOG091G01X1.
PhylomeDBiQ9Z1Z1.
TreeFamiTF101511.

Family and domain databases

Gene3Di2.140.10.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR027295. Quinoprotein_ADH-like_fam.
IPR011047. Quinoprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF50998. SSF50998. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9Z1Z1-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MERATQPRPR ALLLLFLLLG CAAGISAVAR ARSLLAPTSD TAFGLGAAAA
60 70 80 90 100
PTSAARVPAV ATAEVTVEDA EALPAASGEQ ESRATESDDD VELRPRGRSL
110 120 130 140 150
VIISTLDGRI AALDAENHGK KQWDLDVGSG SLVSSSLSKP EVFGNKMIIP
160 170 180 190 200
SLDGDLFQWD RDRESMEAVP FTVESLLESS YKFGDDVVLV GGKSLTTYGL
210 220 230 240 250
SAYSGKLRYI CSALGCRRWD SDEMEEEEDI LLLQRTQKTV RAVGPRSGSE
260 270 280 290 300
KWNFSVGHFE LRYIPDMETR AGFIESTFKL GGNKEDSKII SDVEEQDVDT
310 320 330 340 350
VIKVSVADWK VMAFSKKGGR LEWEYQFCTP IASAWLVRDG KVIPISLFDD
360 370 380 390 400
TSYTANEEVL EDEEDIVEAA RGATENSVYL GMYRGQLYLQ SSVRVSEKFP
410 420 430 440 450
TRPKALESVN GESAIIPLPT IKWKPLIHSP SRTPVLVGSD EFDKCLSNDK
460 470 480 490 500
YSHEEYSNGA LSILQYPYDN GYYLPYYKRE RNKRSTQITV RFLDSPHYSK
510 520 530 540 550
NIRKKDPILL LHWWKEIFGT ILLCIVATTF IVRRLFHPQP HRQRKESETQ
560 570 580 590 600
CQTESKYDSV SADNSDNSWN DIKHSGYVSR YLTDFEPIQC MGRGGFGVVF
610 620 630 640 650
EAKNKVDDCN YAIKRIRLPN RELAREKVMR EVKALAKLEH PGIVRYFNAW
660 670 680 690 700
LETPPEKWQE EMDEIWLKDE STDWPLSSPS PMDAPSVKIR QMDPFSTKEQ
710 720 730 740 750
IEVIAPSPER SRSFSVGISC GRTSSSESQF SPLEFSGTDC GDNSDSEDAA
760 770 780 790 800
HNLQDSCLTD CDMEDGTVDG DDEGHSFELC PSEASPYTRS REGTSSSIVF
810 820 830 840 850
EDSGCDNASS KEDPRMNRLH NGHHYVNKLT EFKHSSSRSS SEATLSTSPT
860 870 880 890 900
RPTTLSLDFT RNTVDRLQPS SPKVYLYIQM QLCRKENLKD WMNRRCSMED
910 920 930 940 950
REHRVCLHIF LQIAEAVQFL HSKGLMHRDL KPSNIFFTMD DVVKVGDFGL
960 970 980 990 1000
VTAMDQDEEE QTVLTPMPAY ATHTGQVGTK LYMSPEQIHG NNYSHKVDIF
1010 1020 1030 1040 1050
SLGLILFELL YPFSTQMERV RTLTDVRNLK FPPLFTQKYP QEHMMVQDML
1060 1070 1080 1090 1100
SPSPMERPEA TDIIENAVFE NLEFPGKTVL RQRSRSLSSS GTKHSRQPSS

TFSPLPGN
Length:1,108
Mass (Da):124,770
Last modified:May 1, 1999 - v1
Checksum:iB3716B1FD26ED32B
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF096835 mRNA. Translation: AAC83801.1.
PIRiT17455.
RefSeqiNP_113787.1. NM_031599.2.
UniGeneiRn.24897.

Genome annotation databases

EnsembliENSRNOT00000008451; ENSRNOP00000008451; ENSRNOG00000006069.
GeneIDi29702.
KEGGirno:29702.
UCSCiRGD:70884. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF096835 mRNA. Translation: AAC83801.1.
PIRiT17455.
RefSeqiNP_113787.1. NM_031599.2.
UniGeneiRn.24897.

3D structure databases

ProteinModelPortaliQ9Z1Z1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008451.

PTM databases

iPTMnetiQ9Z1Z1.
PhosphoSiteiQ9Z1Z1.

Proteomic databases

PaxDbiQ9Z1Z1.
PRIDEiQ9Z1Z1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000008451; ENSRNOP00000008451; ENSRNOG00000006069.
GeneIDi29702.
KEGGirno:29702.
UCSCiRGD:70884. rat.

Organism-specific databases

CTDi9451.
RGDi70884. Eif2ak3.

Phylogenomic databases

eggNOGiKOG1033. Eukaryota.
ENOG410XS0B. LUCA.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000112308.
HOVERGENiHBG051431.
InParanoidiQ9Z1Z1.
KOiK08860.
OMAiKWKPLIH.
OrthoDBiEOG091G01X1.
PhylomeDBiQ9Z1Z1.
TreeFamiTF101511.

Enzyme and pathway databases

ReactomeiR-RNO-381042. PERK regulates gene expression.

Miscellaneous databases

PROiQ9Z1Z1.

Gene expression databases

BgeeiENSRNOG00000006069.
GenevisibleiQ9Z1Z1. RN.

Family and domain databases

Gene3Di2.140.10.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR027295. Quinoprotein_ADH-like_fam.
IPR011047. Quinoprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF50998. SSF50998. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiE2AK3_RAT
AccessioniPrimary (citable) accession number: Q9Z1Z1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: September 7, 2016
This is version 143 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.