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Protein

Eukaryotic translation initiation factor 2-alpha kinase 3

Gene

Eif2ak3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 (PubMed:11106749). 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 (PubMed:23921556). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (PubMed:11035797). Involved in control of mitochondrial morphology and function (PubMed:23921556).3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Activity 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)DescriptionActionsGraphical viewLength
Binding sitei618ATP1
Active sitei935Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi595 – 603ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processStress response, Translation regulation, Unfolded protein response
LigandATP-binding, Nucleotide-binding

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1341830 Eif2ak3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini29 – 510LumenalSequence analysisAdd BLAST482
Transmembranei511 – 531HelicalSequence analysisAdd BLAST21
Topological domaini532 – 1114CytoplasmicSequence analysisAdd BLAST583

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi618K → A: Loss of activity and autophosphorylation. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 28Sequence analysisAdd BLAST28
ChainiPRO_000002432329 – 1114Eukaryotic translation initiation factor 2-alpha kinase 3Add BLAST1086

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi254N-linked (GlcNAc...) asparagine1
Modified residuei615PhosphotyrosineBy similarity1
Modified residuei711PhosphoserineBy similarity1
Modified residuei980Phosphothreonine1 Publication1
Modified residuei1092PhosphoserineBy similarity1

Post-translational modificationi

Autophosphorylated. Phosphorylated at Tyr-615 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity (By similarity). Oligomerization of the N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-980 on the kinase activation loop.By similarity1 Publication
N-glycosylated.
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.By similarity

Keywords - PTMi

ADP-ribosylation, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ9Z2B5
MaxQBiQ9Z2B5
PaxDbiQ9Z2B5
PRIDEiQ9Z2B5

PTM databases

iPTMnetiQ9Z2B5
PhosphoSitePlusiQ9Z2B5

Expressioni

Tissue specificityi

Ubiquitous.

Inductioni

By ER stress.

Interactioni

Subunit structurei

Forms dimers with HSPA5/BIP in resting cells (PubMed:21543844). Oligomerizes in ER-stressed cells (PubMed:10854322). Interacts with DNAJC3 (PubMed:12446838). Interacts with MFN2 (PubMed:23921556). Interacts with TMEM33 (By similarity). Interacts with PDIA6 (By similarity).By similarity4 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-39494N
IntActiQ9Z2B5, 3 interactors
MINTiQ9Z2B5
STRINGi10090.ENSMUSP00000034093

Structurei

Secondary structure

11114
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9Z2B5
SMRiQ9Z2B5
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini589 – 1075Protein kinasePROSITE-ProRule annotationAdd BLAST487

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi48 – 51Poly-Ala4
Compositional biasi224 – 229Poly-Glu6

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

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1033 Eukaryota
ENOG410XS0B LUCA
HOGENOMiHOG000112308
HOVERGENiHBG051431
InParanoidiQ9Z2B5
KOiK08860
PhylomeDBiQ9Z2B5

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR011047 Quinoprotein_ADH-like_supfam
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF50998 SSF50998, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

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

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

Q9Z2B5-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MERATRPGPR ALLLLLFLLL GCAAGISAVA PARSLLAPAS ETVFGLGAAA
60 70 80 90 100
APTSAARVPA VATAEVTVED AEALPAAAGE PESRATEPDD DVELRPRGRS
110 120 130 140 150
LVIISTLDGR IAALDAENDG KKQWDLDVGS GSLVSSSLSK PEVFGNKMII
160 170 180 190 200
PSLDGDLFQW DRDRESMEAV PFTVESLLES SYKFGDDVVL VGGKSLITYG
210 220 230 240 250
LSAYSGKLRY ICSALGCRRW DSDEMEEEED ILLLQRTQKT VRAVGPRSGS
260 270 280 290 300
EKWNFSVGHF ELRYIPDMET RAGFIESTFK PGGNKEDSKI ISDVEEQEAT
310 320 330 340 350
MLDTVIKVSV ADWKVMAFSR KGGRLEWEYQ FCTPIASAWL VRDGKVIPIS
360 370 380 390 400
LFDDTSYTAS EEALGDEEDI VEAARGATEN SVYLGMYRGQ LYLQSSVRVS
410 420 430 440 450
EKFPTSPKAL ESVNGENAII PLPTIKWKPL IHSPSRTPVL VGSDEFDKCL
460 470 480 490 500
SNDKYSHEEY SNGALSILQY PYDNGYYLPY YKRERNKRST QITVRFLDSP
510 520 530 540 550
HYSKNIRKKD PILLLHWWKE IFGTILLCIV ATTFIVRRLF HPQPHRQRKE
560 570 580 590 600
SETQCQTESK YDSVSADVSD NSWNDMKYSG YVSRYLTDFE PIQCMGRGGF
610 620 630 640 650
GVVFEAKNKV DDCNYAIKRI RLPNRELARE KVMREVKALA KLEHPGIVRY
660 670 680 690 700
FNAWLETPPE KWQEEMDEIW LKDESTDWPL SSPSPMDAPS VKIRRMDPFS
710 720 730 740 750
TKEQIEVIAP SPERSRSFSV GISCGQTSSS ESQFSPLEFS GTDCGDNSDS
760 770 780 790 800
ADAAYNLQDS CLTDCEDVED GTVDGNDEGH SFELCPSEAS PYTRSREGTS
810 820 830 840 850
SSIVFEDSGC GNASSKEEPR GNRLHDGNHY VNKLTDLKCS SSRSSSEATT
860 870 880 890 900
LSTSPTRPTT LSLDFTKNTV GQLQPSSPKV YLYIQMQLCR KENLKDWMNR
910 920 930 940 950
RCSLEDREHG VCLHIFLQIA EAVEFLHSKG LMHRDLKPSN IFFTMDDVVK
960 970 980 990 1000
VGDFGLVTAM DQDEEEQTVL TPMPAYATHT GQVGTKLYMS PEQIHGNNYS
1010 1020 1030 1040 1050
HKVDIFSLGL ILFELLYPFS TQMERVRILT DVRNLKFPLL FTQKYPQEHM
1060 1070 1080 1090 1100
MVQDMLSPSP TERPEATDII ENAIFENLEF PGKTVLRQRS RSMSSSGTKH
1110
SRQPSCSYSP LPGN
Length:1,114
Mass (Da):124,682
Last modified:May 1, 1999 - v1
Checksum:i65A47D6C0DD2E046
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9QQ30E9QQ30_MOUSE
Eukaryotic translation initiation f...
Eif2ak3
1,114Annotation score:
A0A0R4J1Y1A0A0R4J1Y1_MOUSE
Eukaryotic translation initiation f...
Eif2ak3
152Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti143 – 152VFGNKMIIPS → GTHKTSSKEC in BAB26908 (PubMed:16141072).Curated10
Sequence conflicti826Missing in BAB22655 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF076681 mRNA Translation: AAD03337.1
AK010397 mRNA Translation: BAB26908.1
AK003226 mRNA Translation: BAB22655.1
CCDSiCCDS20223.1
PIRiT14351
RefSeqiNP_001300847.1, NM_001313918.1
UniGeneiMm.247167

Genome annotation databases

GeneIDi13666
KEGGimmu:13666
UCSCiuc009cgc.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF076681 mRNA Translation: AAD03337.1
AK010397 mRNA Translation: BAB26908.1
AK003226 mRNA Translation: BAB22655.1
CCDSiCCDS20223.1
PIRiT14351
RefSeqiNP_001300847.1, NM_001313918.1
UniGeneiMm.247167

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3QD2X-ray2.81B583-1078[»]
4YZYX-ray3.20A100-399[»]
ProteinModelPortaliQ9Z2B5
SMRiQ9Z2B5
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-39494N
IntActiQ9Z2B5, 3 interactors
MINTiQ9Z2B5
STRINGi10090.ENSMUSP00000034093

PTM databases

iPTMnetiQ9Z2B5
PhosphoSitePlusiQ9Z2B5

Proteomic databases

EPDiQ9Z2B5
MaxQBiQ9Z2B5
PaxDbiQ9Z2B5
PRIDEiQ9Z2B5

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi13666
KEGGimmu:13666
UCSCiuc009cgc.1 mouse

Organism-specific databases

CTDi9451
MGIiMGI:1341830 Eif2ak3

Phylogenomic databases

eggNOGiKOG1033 Eukaryota
ENOG410XS0B LUCA
HOGENOMiHOG000112308
HOVERGENiHBG051431
InParanoidiQ9Z2B5
KOiK08860
PhylomeDBiQ9Z2B5

Miscellaneous databases

PROiPR:Q9Z2B5
SOURCEiSearch...

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR011047 Quinoprotein_ADH-like_supfam
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF50998 SSF50998, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiE2AK3_MOUSE
AccessioniPrimary (citable) accession number: Q9Z2B5
Secondary accession number(s): Q9CTK8, Q9CWT5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: November 7, 2018
This is version 169 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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