Q9NZJ5 (E2AK3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	1116 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 (CCND1) 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 endoplasmic reticulum 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.7 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 Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	ER overload response Inferred from direct assay Ref.2. Source: UniProtKB activation of cysteine-type endopeptidase activity involved in apoptotic process 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 Inferred from direct assay Ref.2. 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 Traceable author statement Ref.2. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.1. Source: UniProtKB protein homooligomerization Inferred from mutant phenotype. Source: UniProtKB
Cellular component	endoplasmic reticulum membrane Inferred from sequence or structural similarity. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW eukaryotic translation initiation factor 2alpha kinase activity Inferred from direct assay Ref.1Ref.2. 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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 29	29	Potential
	Chain	30 – 1116	1087	Eukaryotic translation initiation factor 2-alpha kinase 3		PRO_0000024322
Regions
	Topological domain	30 – 514	485	Lumenal Potential
	Transmembrane	515 – 535	21	Helical; Potential
	Topological domain	536 – 1116	581	Cytoplasmic Potential
	Domain	593 – 1077	485	Protein kinase
	Nucleotide binding	599 – 607	9	ATP By similarity
	Compositional bias	49 – 52	4	Poly-Ala
Sites
	Active site	937	1	Proton acceptor By similarity
	Binding site	622	1	ATP By similarity
Amino acid modifications
	Modified residue	715	1	Phosphoserine Ref.7
	Glycosylation	258	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	136	1	S → C. Ref.3 Ref.8 Corresponds to variant rs867529 [ dbSNP | Ensembl ].		VAR_011409
	Natural variant	166	1	Q → R. Ref.1 Ref.2 Ref.6 Corresponds to variant rs13045 [ dbSNP | Ensembl ].		VAR_011410
	Natural variant	566	1	D → V. Ref.8		VAR_040477
	Natural variant	588	1	R → Q in WRS; in a Pakistani family; probable complete loss of activity. Ref.3		VAR_011408
	Natural variant	704	1	A → S. Ref.1 Ref.2 Ref.6 Corresponds to variant rs1805165 [ dbSNP | Ensembl ].		VAR_011411
	Natural variant	716	1	P → L. Ref.8		VAR_040478
Experimental info
	Sequence conflict	14	1	Missing in AAD19961. Ref.1
	Sequence conflict	14	1	Missing in AAF61199. Ref.2
	Sequence conflict	14	1	Missing in AAF91480. Ref.3
	Sequence conflict	14	1	Missing in BAG37696. Ref.4
	Sequence conflict	14	1	Missing in AAI26357. Ref.6
	Sequence conflict	490	1	N → H in AAF61199. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q9NZJ5 [UniParc]. Last modified May 18, 2010. Version 3. Checksum: 95FEB5DAE8D3D452	FASTA	1,116	125,216
	10 20 30 40 50 60 MERAISPGLL VRALLLLLLL LGLAARTVAA GRARGLPAPT AEAAFGLGAA AAPTSATRVP 70 80 90 100 110 120 AAGAVAAAEV TVEDAEALPA AAGEQEPRGP EPDDETELRP RGRSLVIIST LDGRIAALDP 130 140 150 160 170 180 ENHGKKQWDL DVGSGSLVSS SLSKPEVFGN KMIIPSLDGA LFQWDQDRES METVPFTVES 190 200 210 220 230 240 LLESSYKFGD DVVLVGGKSL TTYGLSAYSG KVRYICSALG CRQWDSDEME QEEDILLLQR 250 260 270 280 290 300 TQKTVRAVGP RSGNEKWNFS VGHFELRYIP DMETRAGFIE STFKPNENTE ESKIISDVEE 310 320 330 340 350 360 QEAAIMDIVI KVSVADWKVM AFSKKGGHLE WEYQFCTPIA SAWLLKDGKV IPISLFDDTS 370 380 390 400 410 420 YTSNDDVLED EEDIVEAARG ATENSVYLGM YRGQLYLQSS VRISEKFPSS PKALESVTNE 430 440 450 460 470 480 NAIIPLPTIK WKPLIHSPSR TPVLVGSDEF DKCLSNDKFS HEEYSNGALS ILQYPYDNGY 490 500 510 520 530 540 YLPYYKRERN KRSTQITVRF LDNPHYNKNI RKKDPVLLLH WWKEIVATIL FCIIATTFIV 550 560 570 580 590 600 RRLFHPHPHR QRKESETQCQ TENKYDSVSG EANDSSWNDI KNSGYISRYL TDFEPIQCLG 610 620 630 640 650 660 RGGFGVVFEA KNKVDDCNYA IKRIRLPNRE LAREKVMREV KALAKLEHPG IVRYFNAWLE 670 680 690 700 710 720 APPEKWQEKM DEIWLKDEST DWPLSSPSPM DAPSVKIRRM DPFATKEHIE IIAPSPQRSR 730 740 750 760 770 780 SFSVGISCDQ TSSSESQFSP LEFSGMDHED ISESVDAAYN LQDSCLTDCD VEDGTMDGND 790 800 810 820 830 840 EGHSFELCPS EASPYVRSRE RTSSSIVFED SGCDNASSKE EPKTNRLHIG NHCANKLTAF 850 860 870 880 890 900 KPTSSKSSSE ATLSISPPRP TTLSLDLTKN TTEKLQPSSP KVYLYIQMQL CRKENLKDWM 910 920 930 940 950 960 NGRCTIEERE RSVCLHIFLQ IAEAVEFLHS KGLMHRDLKP SNIFFTMDDV VKVGDFGLVT 970 980 990 1000 1010 1020 AMDQDEEEQT VLTPMPAYAR HTGQVGTKLY MSPEQIHGNS YSHKVDIFSL GLILFELLYP 1030 1040 1050 1060 1070 1080 FSTQMERVRT LTDVRNLKFP PLFTQKYPCE YVMVQDMLSP SPMERPEAIN IIENAVFEDL 1090 1100 1110 DFPGKTVLRQ RSRSLSSSGT KHSRQSNNSH SPLPSN

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, VARIANTS ARG-166 AND SER-704. 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, VARIANTS ARG-166 AND SER-704. 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-588, VARIANT CYS-136.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[5]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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], VARIANTS ARG-166 AND SER-704.
[7]	"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-715, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"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-136; VAL-566 AND LEU-716.
+	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. AK315287 mRNA. Translation: BAG37696.1. AC062029 Genomic DNA. Translation: AAY14777.1. AC104134 Genomic DNA. Translation: AAY24331.1. BC126354 mRNA. Translation: AAI26355.1. BC126356 mRNA. Translation: AAI26357.1.
IPI	IPI00303053.
RefSeq	NP_004827.4. NM_004836.5.
UniGene	Hs.591589.
3D structure databases
ProteinModelPortal	Q9NZJ5.
SMR	Q9NZJ5. Positions 102-135, 586-1080.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9NZJ5. 6 interactions.
STRING	Q9NZJ5.
PTM databases
PhosphoSite	Q9NZJ5.
Polymorphism databases
DMDM	296439367.
Proteomic databases
PRIDE	Q9NZJ5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000303236; ENSP00000307235; ENSG00000172071.
GeneID	9451.
KEGG	hsa:9451.
Organism-specific databases
CTD	9451.
GeneCards	GC02M088758.
H-InvDB	HIX0023925. HIX0030379.
HGNC	HGNC:3255. EIF2AK3.
HPA	CAB009204. HPA015737.
MIM	226980. phenotype. 604032. gene.
neXtProt	NX_Q9NZJ5.
Orphanet	1667. Wolcott-Rallison syndrome.
GenAtlas	Search...
Phylogenomic databases
GeneTree	ENSGT00530000062984.
HOVERGEN	HBG051431.
InParanoid	Q9NZJ5.
OMA	SDEFDKC.
PhylomeDB	Q9NZJ5.
Enzyme and pathway databases
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. Quinonprotein_ADH-like. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Gene3D	G3DSA:2.140.10.10. Quinoprotein_alc_DH-like. 1 hit.
KO	K08860.
Pfam	PF00069. Pkinase. 2 hits. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50998. Quin_alc_DH_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
SOURCE	Search...

Entry information

Entry name

E2AK3_HUMAN

Accession

Primary (citable) accession number: Q9NZJ5
Secondary accession number(s): A0AVH1 , A0AVH2, B2RCU9, O95846, Q53QY0, Q53SB1

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 26, 2001
Last sequence update:	May 18, 2010
Last modified:	January 25, 2012
This is version 115 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.