Reviewed, UniProtKB/Swiss-Prot Q9NZJ5 (E2AK3_HUMAN)

Names and origin

Protein names

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
      Short name=HsPEK

Gene names

Name:	EIF2AK3
Synonyms:	PEK, PERK

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1115 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Stress response Translation regulation Unfolded protein response
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	ER 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 component	endoplasmic reticulum membrane Non-traceable author statement. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP 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

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-766076,EBI-766076
HSP90B1	P14625	1	EBI-766076,EBI-359129
HSPA5	P11021	1	EBI-766076,EBI-354921

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 28	28	Potential
	Chain	29 – 1115	1087	Eukaryotic translation initiation factor 2-alpha kinase 3		PRO_0000024322
Regions
	Topological domain	29 – 513	485	Lumenal Potential
	Transmembrane	514 – 534	21	Potential
	Topological domain	535 – 1115	581	Cytoplasmic Potential
	Domain	592 – 1076	485	Protein kinase
	Nucleotide binding	598 – 606	9	ATP By similarity
	Compositional bias	48 – 51	4	Poly-Ala
Sites
	Active site	936	1	Proton acceptor By similarity
	Binding site	621	1	ATP By similarity
Amino acid modifications
	Modified residue	714	1	Phosphoserine Ref.5
	Glycosylation	257	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	135	1	S → C: dbSNP rs867529. Ref.3 Ref.6		VAR_011409
	Natural variant	165	1	R → Q: dbSNP rs13045. Ref.3 Ref.6		VAR_011410
	Natural variant	565	1	D → V		VAR_040477
	Natural variant	587	1	R → Q in WRS; in a Pakistani family; probable complete loss of activity. Ref.3		VAR_011408
	Natural variant	703	1	S → A: dbSNP rs1805165. Ref.3 Ref.6		VAR_011411
	Natural variant	715	1	P → L		VAR_040478
Experimental info
	Sequence conflict	489	1	N → H in AAF61199. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q9NZJ5-1 [UniParc]. Last modified September 26, 2001. Version 2. Checksum: 6E4EF99D4CAB8856	FASTA	1,115	125,147
	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

References

	« Hide 'large scale' referencesShow '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. , 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

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF110146 mRNA. Translation: AAD19961.1. AF193339 mRNA. Translation: AAF61199.1. AF284615 , AF284604, AF284605, AF284606, AF284607, AF284608, AF284609, AF284610, AF284611, AF284612, AF284613, AF284614 Genomic DNA. Translation: AAF91480.1. BC126356 mRNA. Translation: AAI26357.1.
IPI	IPI00303053.
UniGene	Hs.591589
3D structure databases
SMR	Q9NZJ5. Positions 103-465, 588-1077.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9NZJ5. 4 interactions.
STRING	Q9NZJ5.
PTM databases
PhosphoSite	Q9NZJ5.
Proteomic databases
PRIDE	Q9NZJ5.
Genome annotation databases
Ensembl	ENST00000303236; ENSP00000307235; ENSG00000172071; Homo sapiens. [Genome view]
Organism-specific databases
GeneCards	GC02M088695.
H-InvDB	HIX0023925. HIX0030379.
HGNC	HGNC:3255. EIF2AK3.
HPA	CAB009204. HPA015737.
MIM	226980. phenotype. 604032. gene.
Orphanet	1667. Wolcott-Rallison syndrome.
PharmGKB	PA27687.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q9NZJ5.
InParanoid	Q9NZJ5.
Enzyme and pathway databases
BRENDA	2.7.11.1. 247.
Reactome	REACT_15380. Diabetes pathways.
Gene expression databases
ArrayExpress	Q9NZJ5.
Bgee	Q9NZJ5.
CleanEx	HS_EIF2AK3.
Genevestigator	Q9NZJ5.
GermOnline	ENSG00000172071. Homo sapiens.
Family and domain databases
InterPro	IPR011009. 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]
Gene3D	G3DSA:2.140.10.10. Quinoprotein_alc_DH-like. 1 hit.
Pfam	PF00069. Pkinase. 2 hits. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

E2AK3_HUMAN

Accession

Primary (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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.