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Reviewed, UniProtKB/Swiss-Prot Q9NZJ5 (E2AK3_HUMAN)

Last modified January 19, 2010. Version 96. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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
      Short name=HsPEK
Gene names
Name: EIF2AK3
Synonyms: PEK, PERK
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1115 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 By similarity.

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 By similarity.

Subunit structure

Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with DNAJC3 By similarity.

Subcellular location

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

Tissue specificity

Ubiquitous. A high level expression is seen in secretory tissues.

Induction

By ER stress.

Domain

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

Post-translational modification

Autophosphorylated. Ref.5

N-glycosylated By similarity.

Involvement in disease

Defects in EIF2AK3 are the cause of Wolcott-Rallison syndrome (WRS) [MIM:226980]; also known as multiple epiphyseal dysplasia with early-onset diabetes mellitus. WRS is a rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. Ref.3

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
   Coding sequence diversityPolymorphism
   DiseaseDiabetes mellitus
Disease mutation
   DomainSignal
Transmembrane
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMGlycoprotein
Phosphoprotein
   Technical termComplete proteome
Gene Ontology (GO)
   Biological processER overload response Ref.2

Inferred from direct assay. Source: UniProtKB

activation of caspase activity

Inferred from sequence or structural similarity. Source: UniProtKB

bone mineralization

Inferred from sequence or structural similarity. Source: UniProtKB

calcium-mediated signaling

Inferred from sequence or structural similarity. Source: UniProtKB

chondrocyte development

Inferred from sequence or structural similarity. Source: UniProtKB

endocrine pancreas development

Inferred from mutant phenotype. Source: UniProtKB

endoplasmic reticulum organization

Inferred from sequence or structural similarity. Source: UniProtKB

endoplasmic reticulum unfolded protein response Ref.2

Inferred from direct assay. Source: UniProtKB

insulin secretion

Inferred from sequence or structural similarity. Source: UniProtKB

insulin-like growth factor receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of myelination

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of translational initiation in response to stress Ref.2

Traceable author statement. Source: UniProtKB

protein amino acid autophosphorylation Ref.1

Inferred from direct assay. Source: UniProtKB

protein homooligomerization

Inferred from mutant phenotype. Source: UniProtKB

   Cellular componentendoplasmic reticulum membrane

Non-traceable author statement. Source: UniProtKB

integral to membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

eukaryotic translation initiation factor 2alpha kinase activity Ref.1 Ref.2

Inferred from direct assay. Source: UniProtKB

identical protein binding

Inferred from physical interaction. Source: IntAct

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2828 Potential
Chain29 – 11151087Eukaryotic translation initiation factor 2-alpha kinase 3
PRO_0000024322

Regions

Topological domain29 – 513485Lumenal Potential
Transmembrane514 – 53421 Potential
Topological domain535 – 1115581Cytoplasmic Potential
Domain592 – 1076485Protein kinase
Nucleotide binding598 – 6069ATP By similarity
Compositional bias48 – 514Poly-Ala

Sites

Active site9361Proton acceptor By similarity
Binding site6211ATP By similarity

Amino acid modifications

Modified residue7141Phosphoserine Ref.5
Glycosylation2571N-linked (GlcNAc...) Potential

Natural variations

Natural variant1351S → C: dbSNP rs867529. Ref.3 Ref.6
VAR_011409
Natural variant1651R → Q: dbSNP rs13045. Ref.3 Ref.6
VAR_011410
Natural variant5651D → V
VAR_040477
Natural variant5871R → Q in WRS; in a Pakistani family; probable complete loss of activity. Ref.3
VAR_011408
Natural variant7031S → A: dbSNP rs1805165. Ref.3 Ref.6
VAR_011411
Natural variant7151P → L
VAR_040478

Experimental info

Sequence conflict4891N → H in AAF61199. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q9NZJ5-1 [UniParc].

Last modified September 26, 2001. Version 2.
Checksum: 6E4EF99D4CAB8856

FASTA1,115125,147
        10         20         30         40         50         60 
MERAISPGLL VRALLLLLLL GLAARTVAAG RARGLPAPTA EAAFGLGAAA APTSATRVPA 

        70         80         90        100        110        120 
AGAVAAAEVT VEDAEALPAA AGEQEPRGPE PDDETELRPR GRSLVIISTL DGRIAALDPE 

       130        140        150        160        170        180 
NHGKKQWDLD VGSGSLVSSS LSKPEVFGNK MIIPSLDGAL FQWDRDRESM ETVPFTVESL 

       190        200        210        220        230        240 
LESSYKFGDD VVLVGGKSLT TYGLSAYSGK VRYICSALGC RQWDSDEMEQ EEDILLLQRT 

       250        260        270        280        290        300 
QKTVRAVGPR SGNEKWNFSV GHFELRYIPD METRAGFIES TFKPNENTEE SKIISDVEEQ 

       310        320        330        340        350        360 
EAAIMDIVIK VSVADWKVMA FSKKGGHLEW EYQFCTPIAS AWLLKDGKVI PISLFDDTSY 

       370        380        390        400        410        420 
TSNDDVLEDE EDIVEAARGA TENSVYLGMY RGQLYLQSSV RISEKFPSSP KALESVTNEN 

       430        440        450        460        470        480 
AIIPLPTIKW KPLIHSPSRT PVLVGSDEFD KCLSNDKFSH EEYSNGALSI LQYPYDNGYY 

       490        500        510        520        530        540 
LPYYKRERNK RSTQITVRFL DNPHYNKNIR KKDPVLLLHW WKEIVATILF CIIATTFIVR 

       550        560        570        580        590        600 
RLFHPHPHRQ RKESETQCQT ENKYDSVSGE ANDSSWNDIK NSGYISRYLT DFEPIQCLGR 

       610        620        630        640        650        660 
GGFGVVFEAK NKVDDCNYAI KRIRLPNREL AREKVMREVK ALAKLEHPGI VRYFNAWLEA 

       670        680        690        700        710        720 
PPEKWQEKMD EIWLKDESTD WPLSSPSPMD APSVKIRRMD PFSTKEHIEI IAPSPQRSRS 

       730        740        750        760        770        780 
FSVGISCDQT SSSESQFSPL EFSGMDHEDI SESVDAAYNL QDSCLTDCDV EDGTMDGNDE 

       790        800        810        820        830        840 
GHSFELCPSE ASPYVRSRER TSSSIVFEDS GCDNASSKEE PKTNRLHIGN HCANKLTAFK 

       850        860        870        880        890        900 
PTSSKSSSEA TLSISPPRPT TLSLDLTKNT TEKLQPSSPK VYLYIQMQLC RKENLKDWMN 

       910        920        930        940        950        960 
GRCTIEERER SVCLHIFLQI AEAVEFLHSK GLMHRDLKPS NIFFTMDDVV KVGDFGLVTA 

       970        980        990       1000       1010       1020 
MDQDEEEQTV LTPMPAYARH TGQVGTKLYM SPEQIHGNSY SHKVDIFSLG LILFELLYPF 

      1030       1040       1050       1060       1070       1080 
STQMERVRTL TDVRNLKFPP LFTQKYPCEY VMVQDMLSPS PMERPEAINI IENAVFEDLD 

      1090       1100       1110 
FPGKTVLRQR SRSLSSSGTK HSRQSNNSHS PLPSN 

« Hide

References

« Hide 'large scale' references
[1]"Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells."
Shi Y., An J., Liang J., Hayes S.E., Sandusky G.E., Stramm L.E., Yang N.N.
J. Biol. Chem. 274:5723-5730(1999) [PubMed: 10026192] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
Tissue: Liver, Pancreas and Testis.
[2]"Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress."
Sood R., Porter A.C., Ma K., Quilliam L.A., Wek R.C.
Biochem. J. 346:281-293(2000) [PubMed: 10677345] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
Tissue: Brain and Pancreas.
[3]"EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome."
Delepine M., Nicolino M., Barrett T., Golamaully M., Lathrop G.M., Julier C.
Nat. Genet. 25:406-409(2000) [PubMed: 10932183] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT WRS GLN-587, VARIANTS CYS-135; GLN-165 AND ALA-703.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-714, MASS SPECTROMETRY.
[6]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed: 17344846] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-135; GLN-165; VAL-565; ALA-703 AND LEU-715.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF110146 mRNA. Translation: AAD19961.1.
AF193339 mRNA. Translation: AAF61199.1.
AF284615 expand/collapse EMBL AC list , AF284604, AF284605, AF284606, AF284607, AF284608, AF284609, AF284610, AF284611, AF284612, AF284613, AF284614 Genomic DNA. Translation: AAF91480.1.
BC126356 mRNA. Translation: AAI26357.1.
IPIIPI00303053.
UniGeneHs.591589

3D structure databases

SMRQ9NZJ5. Positions 103-465, 588-1077.
ModBaseSearch...

Protein-protein interaction databases

IntActQ9NZJ5. 4 interactions.
STRINGQ9NZJ5.

PTM databases

PhosphoSiteQ9NZJ5.

Proteomic databases

PRIDEQ9NZJ5.

Genome annotation databases

EnsemblENST00000303236; ENSP00000307235; ENSG00000172071; Homo sapiens. [Genome view]

Organism-specific databases

GeneCardsGC02M088695.
H-InvDBHIX0023925.
HIX0030379.
HGNCHGNC:3255. EIF2AK3.
HPACAB009204.
HPA015737.
MIM226980. phenotype.
604032. gene.
Orphanet1667. Wolcott-Rallison syndrome.
PharmGKBPA27687.
GenAtlasSearch...

Phylogenomic databases

HOVERGENQ9NZJ5.
InParanoidQ9NZJ5.

Enzyme and pathway databases

BRENDA2.7.11.1. 247.
ReactomeREACT_15380. Diabetes pathways.

Gene expression databases

ArrayExpressQ9NZJ5.
BgeeQ9NZJ5.
CleanExHS_EIF2AK3.
GenevestigatorQ9NZJ5.
GermOnlineENSG00000172071. Homo sapiens.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR011047. Quino_AlcDH-like.
IPR017442. Se/Thr_prot_kinase-like_dom.
IPR008271. Ser/Thr_prot_kinase_AS.
[Graphical view]
Gene3DG3DSA:2.140.10.10. Quinoprotein_alc_DH-like. 1 hit.
PfamPF00069. Pkinase. 2 hits.
[Graphical view]
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

SOURCESearch...

Entry information

Entry nameE2AK3_HUMAN
AccessionPrimary (citable) accession number: Q9NZJ5
Secondary accession number(s): A0AVH2, O95846
Entry history
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: September 26, 2001
Last modified: January 19, 2010
This is version 96 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

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List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents