Q9Z1Z1 (E2AK3_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	1108 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.
Subunit structure	Interacts with DNAJC3 By similarity. Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Ref.3
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-611 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity By similarity. N-glycosylated By similarity. 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	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 electronic annotation. Source: Compara activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from electronic annotation. Source: Compara bone mineralization Inferred from electronic annotation. Source: Compara calcium-mediated signaling Inferred from electronic annotation. Source: Compara chondrocyte development Inferred from electronic annotation. Source: Compara endocrine pancreas development Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum organization Inferred from electronic annotation. Source: Compara endoplasmic reticulum unfolded protein response Inferred from sequence or structural similarity. Source: UniProtKB fat cell differentiation Inferred from electronic annotation. Source: Compara insulin secretion Inferred from electronic annotation. Source: Compara insulin-like growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara lactation Inferred from electronic annotation. Source: Compara negative regulation of myelination Inferred from electronic annotation. Source: Compara negative regulation of translational initiation in response to stress Traceable author statement PubMed 15936177. Source: RGD ossification Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein binding Inferred from electronic annotation. Source: Compara positive regulation of signal transduction Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara translation Inferred from electronic annotation. Source: Compara virus-infected cell apoptotic process Inferred from electronic annotation. Source: Compara
Cellular_component	cell Inferred from direct assay Ref.1. Source: RGD endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell 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...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 27	27	Potential
	Chain	28 – 1108	1081	Eukaryotic translation initiation factor 2-alpha kinase 3		PRO_0000024324
Regions
	Topological domain	28 – 506	479	Lumenal Potential
	Transmembrane	507 – 527	21	Helical; Potential
	Topological domain	528 – 1108	581	Cytoplasmic Potential
	Domain	585 – 1069	485	Protein kinase
	Nucleotide binding	591 – 599	9	ATP By similarity
	Compositional bias	47 – 50	4	Poly-Ala
	Compositional bias	223 – 228	6	Poly-Glu
Sites
	Active site	929	1	Proton acceptor By similarity
	Binding site	614	1	ATP
Amino acid modifications
	Modified residue	611	1	Phosphotyrosine By similarity
	Modified residue	707	1	Phosphoserine By similarity
	Modified residue	974	1	Phosphothreonine By similarity
	Modified residue	1086	1	Phosphoserine By similarity
	Glycosylation	253	1	N-linked (GlcNAc...) Potential
Experimental info
	Mutagenesis	614	1	K → A: Loss of activity. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q9Z1Z1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: B3716B1FD26ED32B	FASTA	1,108	124,770
	10 20 30 40 50 60 MERATQPRPR ALLLLFLLLG CAAGISAVAR ARSLLAPTSD TAFGLGAAAA PTSAARVPAV 70 80 90 100 110 120 ATAEVTVEDA EALPAASGEQ ESRATESDDD VELRPRGRSL VIISTLDGRI AALDAENHGK 130 140 150 160 170 180 KQWDLDVGSG SLVSSSLSKP EVFGNKMIIP SLDGDLFQWD RDRESMEAVP FTVESLLESS 190 200 210 220 230 240 YKFGDDVVLV GGKSLTTYGL SAYSGKLRYI CSALGCRRWD SDEMEEEEDI LLLQRTQKTV 250 260 270 280 290 300 RAVGPRSGSE KWNFSVGHFE LRYIPDMETR AGFIESTFKL GGNKEDSKII SDVEEQDVDT 310 320 330 340 350 360 VIKVSVADWK VMAFSKKGGR LEWEYQFCTP IASAWLVRDG KVIPISLFDD TSYTANEEVL 370 380 390 400 410 420 EDEEDIVEAA RGATENSVYL GMYRGQLYLQ SSVRVSEKFP TRPKALESVN GESAIIPLPT 430 440 450 460 470 480 IKWKPLIHSP SRTPVLVGSD EFDKCLSNDK YSHEEYSNGA LSILQYPYDN GYYLPYYKRE 490 500 510 520 530 540 RNKRSTQITV RFLDSPHYSK NIRKKDPILL LHWWKEIFGT ILLCIVATTF IVRRLFHPQP 550 560 570 580 590 600 HRQRKESETQ CQTESKYDSV SADNSDNSWN DIKHSGYVSR YLTDFEPIQC MGRGGFGVVF 610 620 630 640 650 660 EAKNKVDDCN YAIKRIRLPN RELAREKVMR EVKALAKLEH PGIVRYFNAW LETPPEKWQE 670 680 690 700 710 720 EMDEIWLKDE STDWPLSSPS PMDAPSVKIR QMDPFSTKEQ IEVIAPSPER SRSFSVGISC 730 740 750 760 770 780 GRTSSSESQF SPLEFSGTDC GDNSDSEDAA HNLQDSCLTD CDMEDGTVDG DDEGHSFELC 790 800 810 820 830 840 PSEASPYTRS REGTSSSIVF EDSGCDNASS KEDPRMNRLH NGHHYVNKLT EFKHSSSRSS 850 860 870 880 890 900 SEATLSTSPT RPTTLSLDFT RNTVDRLQPS SPKVYLYIQM QLCRKENLKD WMNRRCSMED 910 920 930 940 950 960 REHRVCLHIF LQIAEAVQFL HSKGLMHRDL KPSNIFFTMD DVVKVGDFGL VTAMDQDEEE 970 980 990 1000 1010 1020 QTVLTPMPAY ATHTGQVGTK LYMSPEQIHG NNYSHKVDIF SLGLILFELL YPFSTQMERV 1030 1040 1050 1060 1070 1080 RTLTDVRNLK FPPLFTQKYP QEHMMVQDML SPSPMERPEA TDIIENAVFE NLEFPGKTVL 1090 1100 RQRSRSLSSS GTKHSRQPSS TFSPLPGN

References

[1]	"Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control." Shi Y., Vattem K.M., Sood R., An J., Liang J., Stramm L.E., Wek R.C. Mol. Cell. Biol. 18:7499-7509(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION. Tissue: Pancreatic islet.
[2]	"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] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF LYS-614.
[3]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF096835 mRNA. Translation: AAC83801.1.
IPI	IPI00230804.
PIR	T17455.
RefSeq	NP_113787.1. NM_031599.2.
UniGene	Rn.24897.
3D structure databases
ProteinModelPortal	Q9Z1Z1.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000008451.
PTM databases
PhosphoSite	Q9Z1Z1.
Proteomic databases
PaxDb	Q9Z1Z1.
PRIDE	Q9Z1Z1.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000008451; ENSRNOP00000008451; ENSRNOG00000006069.
GeneID	29702.
KEGG	rno:29702.
UCSC	RGD:70884. rat.
Organism-specific databases
CTD	9451.
RGD	70884. Eif2ak3.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00530000062984.
HOGENOM	HOG000112308.
HOVERGEN	HBG051431.
InParanoid	Q9Z1Z1.
KO	K08860.
OMA	SPMDAPS.
OrthoDB	EOG4R23T6.
Gene expression databases
Genevestigator	Q9Z1Z1.
GermOnline	ENSRNOG00000006069. Rattus norvegicus.
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
NextBio	610111.

Entry information

Entry name

E2AK3_RAT

Accession

Primary (citable) accession number: Q9Z1Z1

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 26, 2001
Last sequence update:	May 1, 1999
Last modified:	April 3, 2013
This is version 117 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program