Q9Z2B5 (E2AK3_MOUSE) 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

Gene names

Name:	Eif2ak3
Synonyms:	Pek, Perk

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › 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 (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 process	Stress response Translation regulation Unfolded protein response
Cellular component	Endoplasmic reticulum Membrane
Domain	Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	ADP-ribosylation Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER 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 secretion Inferred from mutant phenotype PubMed 11430819PubMed 11997520. Source: MGI insulin-like growth factor receptor signaling pathway Inferred from mutant phenotype PubMed 12865332. Source: MGI lactation Inferred from mutant phenotype PubMed 18852460. 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 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 regulation of fatty acid metabolic process Inferred from mutant phenotype PubMed 18852460. Source: MGI translation Inferred from direct assay PubMed 12388085. Source: MGI virus-infected cell apoptotic process Inferred from mutant phenotype PubMed 15542627. Source: MGI
Cellular_component	endoplasmic reticulum membrane Inferred from direct assay Ref.1. Source: MGI 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 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

Helical; 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

615

1

Phosphotyrosine By similarity

Modified residue

711

1

Phosphoserine By similarity

Modified residue

980

1

Phosphothreonine Ref.7

Modified residue

1092

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

Secondary structure

1

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1114

Helix Strand Turn

Details...

Helix

584 – 588

5

Beta strand

589 – 596

8

Beta strand

601 – 608

8

Turn

609 – 611

3

Beta strand

614 – 621

8

Turn

625 – 627

3

Helix

628 – 639

12

Beta strand

650 – 656

7

Helix

661 – 667

7

Beta strand

881 – 887

7

Helix

894 – 899

6

Helix

904 – 906

3

Helix

909 – 928

20

Helix

938 – 940

3

Beta strand

941 – 943

3

Beta strand

949 – 951

3

Helix

986 – 988

3

Helix

991 – 995

5

Helix

1002 – 1016

15

Helix

1022 – 1033

12

Helix

1039 – 1044

6

Helix

1046 – 1056

11

Helix

1060 – 1062

3

Helix

1066 – 1071

6

Sequences

	Sequence		Length	Mass (Da)
	Q9Z2B5 [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] [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. , 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.

IPI

IPI00131000.

PIR

T14351.

UniGene

Mm.247167.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3QD2	X-ray	2.81	B	583-1078	[»]

ProteinModelPortal

Q9Z2B5.

SMR

Q9Z2B5. Positions 583-668, 826-1078.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9Z2B5. 1 interaction.

STRING

10090.ENSMUSP00000034093.

PTM databases

PhosphoSite

Q9Z2B5.

Proteomic databases

PaxDb

Q9Z2B5.

PRIDE

Q9Z2B5.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000162950; ENSMUSP00000123759; ENSMUSG00000031668.

Organism-specific databases

MGI

MGI:1341830. Eif2ak3.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00530000062984.

HOGENOM

HOG000112308.

HOVERGEN

HBG051431.

InParanoid

Q9Z2B5.

OrthoDB

EOG4R23T6.

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. Quinonprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

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. False negative.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

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:	May 1, 2013
This is version 123 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program