Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q9Z2B5 (E2AK3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Eif2ak3
Synonyms:Pek, Perk
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1114 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Ref.5

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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

Subunit structure

Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with DNAJC3. Ref.4 Ref.6 Ref.7

Subcellular location

Endoplasmic reticulum membrane; Single-pass type I membrane protein.

Tissue specificity

Ubiquitous.

Induction

By ER stress.

Domain

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

Post-translational modification

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. Ref.7

N-glycosylated.

ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processStress response
Translation regulation
Unfolded protein response
   Cellular componentEndoplasmic reticulum
Membrane
   DomainSignal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMADP-ribosylation
Glycoprotein
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processER overload response

Inferred from sequence or structural similarity. Source: UniProtKB

SREBP signaling pathway

Inferred from direct assay PubMed 18852460. Source: MGI

activation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from mutant phenotype PubMed 10882126. Source: MGI

bone mineralization

Inferred from mutant phenotype PubMed 11997520. Source: MGI

calcium-mediated signaling

Inferred from mutant phenotype PubMed 16352659. Source: MGI

chondrocyte development

Inferred from mutant phenotype PubMed 12865332. Source: MGI

endocrine pancreas development

Inferred from sequence or structural similarity. Source: UniProtKB

endoplasmic reticulum organization

Inferred from mutant phenotype PubMed 11430819. Source: MGI

endoplasmic reticulum unfolded protein response

Inferred from sequence or structural similarity. Source: UniProtKB

fat cell differentiation

Inferred from direct assay PubMed 18852460. Source: MGI

insulin-like growth factor receptor signaling pathway

Inferred from mutant phenotype PubMed 12865332. Source: MGI

intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

Inferred from mutant phenotype PubMed 11430819. Source: MGI

lactation

Inferred from mutant phenotype PubMed 18852460. Source: MGI

negative regulation of apoptotic process

Inferred from mutant phenotype PubMed 15542627. Source: MGI

negative regulation of gene expression

Inferred from mutant phenotype PubMed 23152784. Source: MGI

negative regulation of myelination

Inferred from mutant phenotype PubMed 15911877. Source: MGI

negative regulation of translation

Inferred from direct assay Ref.1. Source: MGI

ossification

Inferred from sequence or structural similarity. Source: UniProtKB

pancreas development

Inferred from mutant phenotype PubMed 11997520. Source: MGI

positive regulation of protein binding

Inferred from mutant phenotype PubMed 16352659. Source: MGI

positive regulation of signal transduction

Inferred from direct assay PubMed 18852460. Source: MGI

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein homooligomerization

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 12388085PubMed 14517290Ref.1. Source: MGI

regulation of fatty acid metabolic process

Inferred from mutant phenotype PubMed 18852460. Source: MGI

skeletal system development

Inferred from mutant phenotype PubMed 11997520. Source: MGI

translation

Inferred from direct assay PubMed 12388085. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 11747369. Source: MGI

endoplasmic reticulum

Inferred from direct assay PubMed 11430819PubMed 14517290. Source: MGI

endoplasmic reticulum membrane

Inferred from direct assay Ref.1. Source: MGI

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

eukaryotic translation initiation factor 2alpha kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 12610133PubMed 16288713PubMed 23667408PubMed 23921556. Source: IntAct

protein kinase activity

Inferred from direct assay PubMed 14517290. Source: MGI

protein serine/threonine kinase activity

Inferred from direct assay Ref.1. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

P279585EBI-1226344,EBI-6904269From a different organism.
EIF2S1P051984EBI-1226344,EBI-1056162From a different organism.
Mfn2Q80U632EBI-1226344,EBI-8437663

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2828 Potential
Chain29 – 11141086Eukaryotic translation initiation factor 2-alpha kinase 3
PRO_0000024323

Regions

Topological domain29 – 510482Lumenal Potential
Transmembrane511 – 53121Helical; Potential
Topological domain532 – 1114583Cytoplasmic Potential
Domain589 – 1075487Protein kinase
Nucleotide binding595 – 6039ATP By similarity
Compositional bias48 – 514Poly-Ala
Compositional bias224 – 2296Poly-Glu

Sites

Active site9351Proton acceptor By similarity
Binding site6181ATP

Amino acid modifications

Modified residue6151Phosphotyrosine By similarity
Modified residue7111Phosphoserine By similarity
Modified residue9801Phosphothreonine Ref.7
Modified residue10921Phosphoserine By similarity
Glycosylation2541N-linked (GlcNAc...)

Experimental info

Mutagenesis6181K → A: Loss of activity and autophosphorylation. Ref.1
Sequence conflict143 – 15210VFGNKMIIPS → GTHKTSSKEC in BAB26908. Ref.3
Sequence conflict8261Missing in BAB22655. Ref.3

Secondary structure

............................................. 1114
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9Z2B5 [UniParc].

Last modified May 1, 1999. Version 1.
Checksum: 65A47D6C0DD2E046

FASTA1,114124,682
        10         20         30         40         50         60 
MERATRPGPR ALLLLLFLLL GCAAGISAVA PARSLLAPAS ETVFGLGAAA APTSAARVPA 

        70         80         90        100        110        120 
VATAEVTVED AEALPAAAGE PESRATEPDD DVELRPRGRS LVIISTLDGR IAALDAENDG 

       130        140        150        160        170        180 
KKQWDLDVGS GSLVSSSLSK PEVFGNKMII PSLDGDLFQW DRDRESMEAV PFTVESLLES 

       190        200        210        220        230        240 
SYKFGDDVVL VGGKSLITYG LSAYSGKLRY ICSALGCRRW DSDEMEEEED ILLLQRTQKT 

       250        260        270        280        290        300 
VRAVGPRSGS EKWNFSVGHF ELRYIPDMET RAGFIESTFK PGGNKEDSKI ISDVEEQEAT 

       310        320        330        340        350        360 
MLDTVIKVSV ADWKVMAFSR KGGRLEWEYQ FCTPIASAWL VRDGKVIPIS LFDDTSYTAS 

       370        380        390        400        410        420 
EEALGDEEDI VEAARGATEN SVYLGMYRGQ LYLQSSVRVS EKFPTSPKAL ESVNGENAII 

       430        440        450        460        470        480 
PLPTIKWKPL IHSPSRTPVL VGSDEFDKCL SNDKYSHEEY SNGALSILQY PYDNGYYLPY 

       490        500        510        520        530        540 
YKRERNKRST QITVRFLDSP HYSKNIRKKD PILLLHWWKE IFGTILLCIV ATTFIVRRLF 

       550        560        570        580        590        600 
HPQPHRQRKE SETQCQTESK YDSVSADVSD NSWNDMKYSG YVSRYLTDFE PIQCMGRGGF 

       610        620        630        640        650        660 
GVVFEAKNKV DDCNYAIKRI RLPNRELARE KVMREVKALA KLEHPGIVRY FNAWLETPPE 

       670        680        690        700        710        720 
KWQEEMDEIW LKDESTDWPL SSPSPMDAPS VKIRRMDPFS TKEQIEVIAP SPERSRSFSV 

       730        740        750        760        770        780 
GISCGQTSSS ESQFSPLEFS GTDCGDNSDS ADAAYNLQDS CLTDCEDVED GTVDGNDEGH 

       790        800        810        820        830        840 
SFELCPSEAS PYTRSREGTS SSIVFEDSGC GNASSKEEPR GNRLHDGNHY VNKLTDLKCS 

       850        860        870        880        890        900 
SSRSSSEATT LSTSPTRPTT LSLDFTKNTV GQLQPSSPKV YLYIQMQLCR KENLKDWMNR 

       910        920        930        940        950        960 
RCSLEDREHG VCLHIFLQIA EAVEFLHSKG LMHRDLKPSN IFFTMDDVVK VGDFGLVTAM 

       970        980        990       1000       1010       1020 
DQDEEEQTVL TPMPAYATHT GQVGTKLYMS PEQIHGNNYS HKVDIFSLGL ILFELLYPFS 

      1030       1040       1050       1060       1070       1080 
TQMERVRILT DVRNLKFPLL FTQKYPQEHM MVQDMLSPSP TERPEATDII ENAIFENLEF 

      1090       1100       1110 
PGKTVLRQRS RSMSSSGTKH SRQPSCSYSP LPGN 

« Hide

References

« Hide 'large scale' references
[1]"Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase."
Harding H.P., Zhang Y., Ron D.
Nature 397:271-274(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF LYS-618.
Strain: NIH Swiss.
Tissue: Fibroblast.
[2]Erratum
Harding H.P., Zhang Y., Ron D.
Nature 398:90-90(1999)
[3]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-152 AND 769-1114.
Strain: C57BL/6J.
[4]"Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response."
Bertolotti A., Zhang Y., Hendershot L.M., Harding H.P., Ron D.
Nat. Cell Biol. 2:326-332(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT.
[5]"PERK mediates cell-cycle exit during the mammalian unfolded protein response."
Brewer J.W., Diehl J.A.
Proc. Natl. Acad. Sci. U.S.A. 97:12625-12630(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK."
Yan W., Frank C.L., Korth M.J., Sopher B.L., Novoa I., Ron D., Katze M.G.
Proc. Natl. Acad. Sci. U.S.A. 99:15920-15925(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DNAJC3.
[7]"The structure of the PERK kinase domain suggests the mechanism for its activation."
Cui W., Li J., Ron D., Sha B.
Acta Crystallogr. D 67:423-428(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) OF 583-701 AND 867-1078, SUBUNIT, PHOSPHORYLATION AT THR-980.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF076681 mRNA. Translation: AAD03337.1.
AK010397 mRNA. Translation: BAB26908.1.
AK003226 mRNA. Translation: BAB22655.1.
CCDSCCDS20223.1.
PIRT14351.
UniGeneMm.247167.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3QD2X-ray2.81B583-1078[»]
ProteinModelPortalQ9Z2B5.
SMRQ9Z2B5. Positions 99-213, 583-668, 826-1103.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ9Z2B5. 3 interactions.
STRING10090.ENSMUSP00000034093.

PTM databases

PhosphoSiteQ9Z2B5.

Proteomic databases

PaxDbQ9Z2B5.
PRIDEQ9Z2B5.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000162950; ENSMUSP00000123759; ENSMUSG00000031668.
UCSCuc009cgc.1. mouse.

Organism-specific databases

MGIMGI:1341830. Eif2ak3.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00530000062984.
HOGENOMHOG000112308.
HOVERGENHBG051431.
InParanoidQ9Z2B5.
PhylomeDBQ9Z2B5.

Gene expression databases

ArrayExpressQ9Z2B5.
BgeeQ9Z2B5.
GenevestigatorQ9Z2B5.

Family and domain databases

Gene3D2.140.10.10. 1 hit.
InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR027295. Quinonprotein_ADH-like_fam.
IPR011047. Quinonprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 2 hits.
[Graphical view]
SUPFAMSSF50998. SSF50998. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

PROQ9Z2B5.
SOURCESearch...

Entry information

Entry nameE2AK3_MOUSE
AccessionPrimary (citable) accession number: Q9Z2B5
Secondary accession number(s): Q9CTK8, Q9CWT5
Entry history
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: July 9, 2014
This is version 135 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot