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Protein

Eukaryotic translation initiation factor 2-alpha kinase 3

Gene

Eif2ak3

Organism
Mus musculus (Mouse)
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 (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.

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)DescriptionActionsGraphical viewLength
Binding sitei618ATP1
Active sitei935Proton acceptorPROSITE-ProRule annotation1

Regions

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

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • enzyme binding Source: MGI
  • eukaryotic initiation factor eIF2 binding Source: ParkinsonsUK-UCL
  • eukaryotic translation initiation factor 2alpha kinase activity Source: UniProtKB
  • protein kinase activity Source: ParkinsonsUK-UCL
  • protein phosphatase binding Source: MGI
  • protein serine/threonine kinase activity Source: MGI

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • angiogenesis Source: MGI
  • bone mineralization Source: MGI
  • calcium-mediated signaling Source: MGI
  • cellular response to amino acid starvation Source: UniProtKB
  • cellular response to cold Source: UniProtKB
  • cellular response to glucose starvation Source: ParkinsonsUK-UCL
  • chondrocyte development Source: MGI
  • eiF2alpha phosphorylation in response to endoplasmic reticulum stress Source: UniProtKB
  • endocrine pancreas development Source: UniProtKB
  • endoplasmic reticulum organization Source: MGI
  • endoplasmic reticulum unfolded protein response Source: UniProtKB
  • ER overload response Source: UniProtKB
  • fat cell differentiation Source: MGI
  • insulin-like growth factor receptor signaling pathway Source: MGI
  • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: MGI
  • lactation Source: MGI
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of gene expression Source: MGI
  • negative regulation of myelination Source: MGI
  • negative regulation of translation Source: AgBase
  • negative regulation of translation in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • ossification Source: UniProtKB
  • pancreas development Source: MGI
  • peptidyl-serine phosphorylation Source: ParkinsonsUK-UCL
  • PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
  • positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: MGI
  • positive regulation of gene expression Source: ParkinsonsUK-UCL
  • positive regulation of glutathione biosynthetic process Source: ParkinsonsUK-UCL
  • positive regulation of protein binding Source: MGI
  • positive regulation of protein localization to nucleus Source: ParkinsonsUK-UCL
  • positive regulation of signal transduction Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • positive regulation of transcription from RNA polymerase I promoter Source: ParkinsonsUK-UCL
  • positive regulation of vascular endothelial growth factor production Source: ParkinsonsUK-UCL
  • protein autophosphorylation Source: UniProtKB
  • protein homooligomerization Source: UniProtKB
  • protein phosphorylation Source: ParkinsonsUK-UCL
  • regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation Source: UniProtKB
  • regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: MGI
  • regulation of fatty acid metabolic process Source: MGI
  • regulation of translational initiation by eIF2 alpha phosphorylation Source: UniProtKB
  • response to endoplasmic reticulum stress Source: UniProtKB
  • skeletal system development Source: MGI
  • SREBP signaling pathway Source: MGI
  • translation Source: MGI
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

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1341830. Eif2ak3.

Subcellular locationi

Topology

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

GO - Cellular componenti

  • cytoplasm Source: MGI
  • endoplasmic reticulum Source: MGI
  • endoplasmic reticulum membrane Source: MGI
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: MGI
Complete GO annotation...

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...)1
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.

Gene expression databases

BgeeiENSMUSG00000031668.

Interactioni

Subunit structurei

Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with DNAJC3 and MFN2. Interacts with TMEM33 (By similarity).By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
P279585EBI-1226344,EBI-6904269From a different organism.
EIF2S1P051984EBI-1226344,EBI-1056162From a different organism.
Mfn2Q80U632EBI-1226344,EBI-8437663

GO - Molecular functioni

  • enzyme binding Source: MGI
  • eukaryotic initiation factor eIF2 binding Source: ParkinsonsUK-UCL
  • protein phosphatase binding Source: MGI

Protein-protein interaction databases

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

Structurei

Secondary structure

11114
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi101 – 106Combined sources6
Beta strandi109 – 114Combined sources6
Beta strandi123 – 127Combined sources5
Beta strandi133 – 136Combined sources4
Beta strandi189 – 192Combined sources4
Beta strandi195 – 201Combined sources7
Beta strandi209 – 212Combined sources4
Beta strandi217 – 219Combined sources3
Beta strandi232 – 244Combined sources13
Beta strandi252 – 264Combined sources13
Beta strandi306 – 309Combined sources4
Turni310 – 313Combined sources4
Beta strandi314 – 317Combined sources4
Beta strandi320 – 322Combined sources3
Beta strandi327 – 330Combined sources4
Beta strandi335 – 345Combined sources11
Helixi584 – 588Combined sources5
Beta strandi589 – 596Combined sources8
Beta strandi601 – 608Combined sources8
Turni609 – 611Combined sources3
Beta strandi614 – 621Combined sources8
Turni625 – 627Combined sources3
Helixi628 – 639Combined sources12
Beta strandi650 – 656Combined sources7
Helixi661 – 667Combined sources7
Beta strandi881 – 887Combined sources7
Helixi894 – 899Combined sources6
Helixi904 – 906Combined sources3
Helixi909 – 928Combined sources20
Helixi938 – 940Combined sources3
Beta strandi941 – 943Combined sources3
Beta strandi949 – 951Combined sources3
Helixi986 – 988Combined sources3
Helixi991 – 995Combined sources5
Helixi1002 – 1016Combined sources15
Helixi1022 – 1033Combined sources12
Helixi1039 – 1044Combined sources6
Helixi1046 – 1056Combined sources11
Helixi1060 – 1062Combined sources3
Helixi1066 – 1071Combined sources6

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...

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
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1033. Eukaryota.
ENOG410XS0B. LUCA.
HOGENOMiHOG000112308.
HOVERGENiHBG051431.
InParanoidiQ9Z2B5.
KOiK08860.
PhylomeDBiQ9Z2B5.

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.

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

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.

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.
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

PROiQ9Z2B5.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000031668.

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_MOUSE
AccessioniPrimary (citable) accession number: Q9Z2B5
Secondary accession number(s): Q9CTK8, Q9CWT5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: November 30, 2016
This is version 158 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

3D-structure, Complete proteome, Reference proteome

Documents

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