Q03963 (E2AK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Interferon-induced, double-stranded RNA-activated protein kinase
EC=2.7.11.1

Alternative name(s):
Eukaryotic translation initiation factor 2-alpha kinase 2
Short name=eIF-2A protein kinase 2
Interferon-inducible RNA-dependent protein kinase
P1/eIF-2A protein kinase
Protein kinase RNA-activated
Short name=PKR
Serine/threonine-protein kinase TIK
Tyrosine-protein kinase EIF2AK2
EC=2.7.10.2
p68 kinase

Gene names

Name:	Eif2ak2
Synonyms:	Pkr, Prkr, Tik

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	515 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	Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Activity is markedly stimulated by manganese ions. Besides dsRNA, heparin is a potent activator of the kinase By similarity.
Subunit structure	Homodimer. Interacts with DNAJC3 and STRBP By similarity. Forms a complex with FANCA, FANCC, FANCG and HSP70 By similarity. Interacts with ADAR/ADAR1. Ref.6
Tissue specificity	Expressed in heart, lung, brain, kidney, testes, thymus and bone marrow.
Induction	By interferon.
Post-translational modification	Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-414 is dependent on Thr-409 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. Contains 2 DRBM (double-stranded RNA-binding) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Antiviral defense
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding RNA-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW endoplasmic reticulum unfolded protein response Inferred from direct assay PubMed 15545996. Source: MGI negative regulation of osteoblast proliferation Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from direct assay PubMed 15545996PubMed 7519779. Source: MGI translation Inferred from direct assay PubMed 7519779. Source: MGI virus-infected cell apoptotic process Inferred from direct assay PubMed 15545996. Source: MGI
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW double-stranded RNA binding Inferred from direct assay PubMed 21703541. Source: MGI non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein kinase activity Inferred from direct assay PubMed 15545996PubMed 7519779. Source: MGI protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Irs1	P35569	2	EBI-2603444,EBI-400825

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed By similarity

Chain

2 – 515

514

Interferon-induced, double-stranded RNA-activated protein kinase

PRO_0000085946

Regions

Domain

8 – 76

69

DRBM 1

Domain

95 – 162

68

DRBM 2

Domain

242 – 504

263

Protein kinase

Nucleotide binding

248 – 256

9

ATP By similarity

Compositional bias

183 – 187

5

Poly-Ser

Compositional bias

241 – 247

7

Asp/Glu-rich (acidic)

Sites

Active site

376

1

Proton acceptor By similarity

Binding site

271

1

ATP By similarity

Amino acid modifications

Modified residue

2

1

N-acetylalanine By similarity

Modified residue

96

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

157

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

268

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

409

1

Phosphothreonine; by autocatalysis By similarity

Modified residue

414

1

Phosphothreonine; by autocatalysis By similarity

Modified residue

419

1

Phosphoserine By similarity

Experimental info

Sequence conflict

52

1

P → G in AAA40150. Ref.1

Sequence conflict

60

1

Q → T in AAA40150. Ref.1

Sequence conflict

87

1

S → C in AAA40150. Ref.1

Sequence conflict

144

1

T → I in AAA39885. Ref.2

Sequence conflict

281 – 282

2

EH → DR in AAA39885. Ref.2

Sequence conflict

510

1

K → E in AAA40150. Ref.1

Sequence conflict

512 – 515

4

RNTC → KHMLGPF Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

515

Helix Strand Turn

Details...

Helix

8 – 20

13

Beta strand

24 – 33

10

Beta strand

35 – 37

3

Beta strand

39 – 48

10

Beta strand

54 – 58

5

Helix

59 – 74

16

Helix

96 – 106

11

Beta strand

111 – 115

5

Beta strand

119 – 123

5

Beta strand

126 – 134

9

Beta strand

136 – 144

9

Helix

145 – 162

18

Sequences

	Sequence		Length	Mass (Da)
	Q03963 [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 7A116F7D8DB9B847	FASTA	515	58,280
	10 20 30 40 50 60 MASDTPGFYM DKLNKYRQMH GVAITYKELS TSGPPHDRRF TFQVLIDEKE FPEAKGRSKQ 70 80 90 100 110 120 EARNAAAKLA VDILDNENKV DCHTSASEQG LFVGNYIGLV NSFAQKKKLS VNYEQCEPNS 130 140 150 160 170 180 ELPQRFICKC KIGQTMYGTG SGVTKQEAKQ LAAKEAYQKL LKSPPKTAGT SSSVVTSTFS 190 200 210 220 230 240 GFSSSSSMTS NGVSQSAPGS FSSENVFTNG LGENKRKSGV KVSPDDVQRN KYTLDARFNS 250 260 270 280 290 300 DFEDIEEIGL GGFGQVFKAK HRIDGKRYAI KRVKYNTEKA EHEVQALAEL NHVNIVQYHS 310 320 330 340 350 360 CWEGVDYDPE HSMSDTSRYK TRCLFIQMEF CDKGTLEQWM RNRNQSKVDK ALILDLYEQI 370 380 390 400 410 420 VTGVEYIHSK GLIHRDLKPG NIFLVDERHI KIGDFGLATA LENDGKSRTR RTGTLQYMSP 430 440 450 460 470 480 EQLFLKHYGK EVDIFALGLI LAELLHTCFT ESEKIKFFES LRKGDFSNDI FDNKEKSLLK 490 500 510 KLLSEKPKDR PETSEILKTL AEWRNISEKK KRNTC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TIK, a novel serine/threonine kinase, is recognized by antibodies directed against phosphotyrosine." Icely P.L., Gros P., Bergeron J.J.M., Devault A., Afar D.E.H., Bell J.C. J. Biol. Chem. 266:16073-16077(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase." Feng G.S., Chong K., Kumar A., Williams B.R.G. Proc. Natl. Acad. Sci. U.S.A. 89:5447-5451(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Mammary carcinoma.
[3]	"Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase." Tanaka H., Samuel C.E. Proc. Natl. Acad. Sci. U.S.A. 91:7995-7999(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: DBA/2J. Tissue: Liver.
[4]	"Sequence of the murine interferon-inducible RNA-dependent protein kinase (PKR) deduced from genomic clones." Tanaka H., Samuel C.E. Gene 153:283-284(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: DBA/2J. Tissue: Liver.
[5]	"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]. Strain: C57BL/6J. Tissue: Skin.
[6]	"Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection." Nie Y., Hammond G.L., Yang J.H. J. Virol. 81:917-923(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ADAR.
[7]	"Solution structure of the first and second DSRM domain in interferon-induced, double-stranded RNA-activated protein kinase." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 1-171.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M65029 mRNA. Translation: AAA40150.1.
M93567 mRNA. Translation: AAA39885.1.
U09928 , U09914, U09915, U09916, U09917, U09918, U09919, U09920, U09921, U09922, U09923, U09924, U09925, U09926, U09927 Genomic DNA. Translation: AAC24729.1.
AK028602 mRNA. Translation: BAC26027.1.

IPI

IPI00138256.

PIR

A59309.

RefSeq

NP_035293.1. NM_011163.4.

UniGene

Mm.378990.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1X48	NMR	-	A	96-171	[»]
1X49	NMR	-	A	1-85	[»]

ProteinModelPortal

Q03963.

SMR

Q03963. Positions 1-171, 190-504.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q03963. 2 interactions.

PTM databases

PhosphoSite

Q03963.

Proteomic databases

PaxDb

Q03963.

PRIDE

Q03963.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000024884; ENSMUSP00000024884; ENSMUSG00000024079.

GeneID

19106.

KEGG

mmu:19106.

UCSC

uc008dph.2. mouse.

Organism-specific databases

CTD

5610.

MGI

MGI:1353449. Eif2ak2.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00530000062984.

HOGENOM

HOG000234351.

HOVERGEN

HBG051430.

InParanoid

Q03963.

KO

K16195.

OMA

MNGLRNN.

OrthoDB

EOG4548ZD.

Gene expression databases

Bgee

Q03963.

Genevestigator

Q03963.

GermOnline

ENSMUSG00000024079. Mus musculus.

Family and domain databases

Gene3D

3.30.160.20. 2 hits.

InterPro

IPR001159. Ds-RNA-bd.
IPR014720. dsRNA-bd-like_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00035. dsrm. 2 hits.
PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00358. DSRM. 2 hits.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS50137. DS_RBD. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1795121.

EvolutionaryTrace

Q03963.

NextBio

295666.

SOURCE

Search...

Entry information

Entry name

E2AK2_MOUSE

Accession

Primary (citable) accession number: Q03963
Secondary accession number(s): Q61742, Q62026

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	November 1, 1997
Last modified:	May 1, 2013
This is version 130 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program