Reviewed, UniProtKB/Swiss-Prot Q9Z2B5 (E2AK3_MOUSE)

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

Gene names

Name:	Eif2ak3
Synonyms:	Pek, Perk

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	1114 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. 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
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. N-glycosylated.
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
Domain	Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Glycoprotein Phosphoprotein
Gene Ontology (GO)
Biological process	ER overload response Inferred from sequence or structural similarity. Source: UniProtKB SREBP-mediated signaling pathway Inferred from direct assay. Source: MGI activation of caspase activity Inferred from mutant phenotype. Source: MGI bone mineralization Inferred from mutant phenotype. Source: MGI calcium-mediated signaling Inferred from mutant phenotype. Source: MGI chondrocyte development Inferred from mutant phenotype. Source: MGI endocrine pancreas development Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum organization Inferred from mutant phenotype. Source: MGI endoplasmic reticulum unfolded protein response Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB fat cell differentiation Inferred from direct assay. Source: MGI insulin secretion Inferred from mutant phenotype. Source: MGI insulin-like growth factor receptor signaling pathway Inferred from mutant phenotype. Source: MGI lactation Inferred from mutant phenotype. Source: MGI negative regulation of myelination Inferred from mutant phenotype. Source: MGI negative regulation of translation Ref.1 Inferred from direct assay. Source: MGI positive regulation of protein binding Inferred from mutant phenotype. Source: MGI positive regulation of signal transduction Inferred from direct assay. Source: MGI protein amino acid autophosphorylation Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB protein homooligomerization Inferred from sequence or structural similarity. Source: UniProtKB regulation of fatty acid metabolic process Inferred from mutant phenotype. Source: MGI translation Inferred from direct assay. Source: MGI virus-infected cell apoptosis Inferred from mutant phenotype. Source: MGI
Cellular component	endoplasmic reticulum membrane Ref.1 Inferred from direct assay. Source: MGI 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 Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
EIF2S1	P05198	4	EBI-1226344,EBI-1056162	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 28	28	Potential
	Chain	29 – 1114	1086	Eukaryotic translation initiation factor 2-alpha kinase 3		PRO_0000024323
Regions
	Topological domain	29 – 510	482	Lumenal Potential
	Transmembrane	511 – 531	21	Potential
	Topological domain	532 – 1114	583	Cytoplasmic Potential
	Domain	589 – 1075	487	Protein kinase
	Nucleotide binding	595 – 603	9	ATP By similarity
	Compositional bias	48 – 51	4	Poly-Ala
	Compositional bias	224 – 229	6	Poly-Glu
Sites
	Active site	935	1	Proton acceptor By similarity
	Binding site	618	1	ATP
Amino acid modifications
	Modified residue	711	1	Phosphoserine By similarity
	Glycosylation	254	1	N-linked (GlcNAc...)
Experimental info
	Mutagenesis	618	1	K → A: Loss of activity and autophosphorylation. Ref.1
	Sequence conflict	143 – 152	10	VFGNKMIIPS → GTHKTSSKEC in BAB26908. Ref.3
	Sequence conflict	826	1	Missing in BAB22655. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q9Z2B5-1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: 65A47D6C0DD2E046	FASTA	1,114	124,682
	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

References

	« Hide 'large scale' referencesShow '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: 9930704] [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. , 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: 16141072] [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: 10854322] [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: 11035797] [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: 12446838] [Abstract] Cited for: INTERACTION WITH DNAJC3.
+	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.
IPI	IPI00131000.
PIR	T14351.
UniGene	Mm.247167
3D structure databases
SMR	Q9Z2B5. Positions 100-461, 585-1077.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Z2B5. 1 interaction.
STRING	Q9Z2B5.
PTM databases
PhosphoSite	Q9Z2B5.
Proteomic databases
PRIDE	Q9Z2B5.
Genome annotation databases
Ensembl	ENSMUST00000034093; ENSMUSP00000034093; ENSMUSG00000031668; Mus musculus. [Genome view]
Organism-specific databases
MGI	MGI:1341830. Eif2ak3.
Phylogenomic databases
HOGENOM	HBG356284.
HOVERGEN	Q9Z2B5.
InParanoid	Q9Z2B5.
Enzyme and pathway databases
BRENDA	2.7.11.1. 244.
Gene expression databases
ArrayExpress	Q9Z2B5.
Bgee	Q9Z2B5.
Genevestigator	Q9Z2B5.
GermOnline	ENSMUSG00000031668. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR011047. Quino_AlcDH-like. IPR017442. Se/Thr_prot_kinase-like_dom. IPR008271. Ser/Thr_prot_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 2 hits. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. False negative. 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_MOUSE

Accession

Primary (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:	January 19, 2010
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)