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Q9Z2B5

- E2AK3_MOUSE

UniProt

Q9Z2B5 - E2AK3_MOUSE

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Protein
Eukaryotic translation initiation factor 2-alpha kinase 3
Gene
Eif2ak3, Pek, Perk
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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).1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in transautophosphorylation and kinase activity induction.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei618 – 6181ATP
Active sitei935 – 9351Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi595 – 6039ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. eukaryotic translation initiation factor 2alpha kinase activity Source: UniProtKB
  3. protein binding Source: IntAct
  4. protein kinase activity Source: MGI
  5. protein serine/threonine kinase activity Source: MGI
Complete GO annotation...

GO - Biological processi

  1. ER overload response Source: UniProtKB
  2. SREBP signaling pathway Source: MGI
  3. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  4. bone mineralization Source: MGI
  5. calcium-mediated signaling Source: MGI
  6. chondrocyte development Source: MGI
  7. endocrine pancreas development Source: UniProtKB
  8. endoplasmic reticulum organization Source: MGI
  9. endoplasmic reticulum unfolded protein response Source: UniProtKB
  10. fat cell differentiation Source: MGI
  11. insulin-like growth factor receptor signaling pathway Source: MGI
  12. intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: MGI
  13. lactation Source: MGI
  14. negative regulation of apoptotic process Source: MGI
  15. negative regulation of gene expression Source: MGI
  16. negative regulation of myelination Source: MGI
  17. negative regulation of translation Source: MGI
  18. ossification Source: UniProtKB
  19. pancreas development Source: MGI
  20. positive regulation of protein binding Source: MGI
  21. positive regulation of signal transduction Source: MGI
  22. protein autophosphorylation Source: UniProtKB
  23. protein homooligomerization Source: UniProtKB
  24. protein phosphorylation Source: MGI
  25. regulation of fatty acid metabolic process Source: MGI
  26. skeletal system development Source: MGI
  27. translation Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Stress response, Translation regulation, Unfolded protein response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
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 namesi
Name:Eif2ak3
Synonyms:Pek, Perk
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 6

Organism-specific databases

MGIiMGI:1341830. Eif2ak3.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini29 – 510482Lumenal Reviewed prediction
Add
BLAST
Transmembranei511 – 53121Helical; Reviewed prediction
Add
BLAST
Topological domaini532 – 1114583Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. cytoplasm Source: MGI
  2. endoplasmic reticulum Source: MGI
  3. endoplasmic reticulum membrane Source: MGI
  4. integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi618 – 6181K → A: Loss of activity and autophosphorylation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2828 Reviewed prediction
Add
BLAST
Chaini29 – 11141086Eukaryotic translation initiation factor 2-alpha kinase 3
PRO_0000024323Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi254 – 2541N-linked (GlcNAc...)
Modified residuei615 – 6151Phosphotyrosine By similarity
Modified residuei711 – 7111Phosphoserine By similarity
Modified residuei980 – 9801Phosphothreonine1 Publication
Modified residuei1092 – 10921Phosphoserine By similarity

Post-translational modificationi

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.1 Publication
N-glycosylated.
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity By similarity.

Keywords - PTMi

ADP-ribosylation, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9Z2B5.
PRIDEiQ9Z2B5.

PTM databases

PhosphoSiteiQ9Z2B5.

Expressioni

Tissue specificityi

Ubiquitous.

Inductioni

By ER stress.

Gene expression databases

ArrayExpressiQ9Z2B5.
BgeeiQ9Z2B5.
GenevestigatoriQ9Z2B5.

Interactioni

Subunit structurei

Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with DNAJC3.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
P279585EBI-1226344,EBI-6904269From a different organism.
EIF2S1P051984EBI-1226344,EBI-1056162From a different organism.
Mfn2Q80U632EBI-1226344,EBI-8437663

Protein-protein interaction databases

IntActiQ9Z2B5. 3 interactions.
STRINGi10090.ENSMUSP00000034093.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi584 – 5885
Beta strandi589 – 5968
Beta strandi601 – 6088
Turni609 – 6113
Beta strandi614 – 6218
Turni625 – 6273
Helixi628 – 63912
Beta strandi650 – 6567
Helixi661 – 6677
Beta strandi881 – 8877
Helixi894 – 8996
Helixi904 – 9063
Helixi909 – 92820
Helixi938 – 9403
Beta strandi941 – 9433
Beta strandi949 – 9513
Helixi986 – 9883
Helixi991 – 9955
Helixi1002 – 101615
Helixi1022 – 103312
Helixi1039 – 10446
Helixi1046 – 105611
Helixi1060 – 10623
Helixi1066 – 10716

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3QD2X-ray2.81B583-1078[»]
ProteinModelPortaliQ9Z2B5.
SMRiQ9Z2B5. Positions 99-213, 583-668, 826-1103.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini589 – 1075487Protein kinase
Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi48 – 514Poly-Ala
Compositional biasi224 – 2296Poly-Glu

Domaini

The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00530000062984.
HOGENOMiHOG000112308.
HOVERGENiHBG051431.
InParanoidiQ9Z2B5.
PhylomeDBiQ9Z2B5.

Family and domain databases

Gene3Di2.140.10.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR027295. Quinonprotein_ADH-like_fam.
IPR011047. Quinonprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SUPFAMiSSF50998. SSF50998. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9Z2B5-1 [UniParc]FASTAAdd to Basket

« Hide

MERATRPGPR ALLLLLFLLL GCAAGISAVA PARSLLAPAS ETVFGLGAAA     50
APTSAARVPA VATAEVTVED AEALPAAAGE PESRATEPDD DVELRPRGRS 100
LVIISTLDGR IAALDAENDG KKQWDLDVGS GSLVSSSLSK PEVFGNKMII 150
PSLDGDLFQW DRDRESMEAV PFTVESLLES SYKFGDDVVL VGGKSLITYG 200
LSAYSGKLRY ICSALGCRRW DSDEMEEEED ILLLQRTQKT VRAVGPRSGS 250
EKWNFSVGHF ELRYIPDMET RAGFIESTFK PGGNKEDSKI ISDVEEQEAT 300
MLDTVIKVSV ADWKVMAFSR KGGRLEWEYQ FCTPIASAWL VRDGKVIPIS 350
LFDDTSYTAS EEALGDEEDI VEAARGATEN SVYLGMYRGQ LYLQSSVRVS 400
EKFPTSPKAL ESVNGENAII PLPTIKWKPL IHSPSRTPVL VGSDEFDKCL 450
SNDKYSHEEY SNGALSILQY PYDNGYYLPY YKRERNKRST QITVRFLDSP 500
HYSKNIRKKD PILLLHWWKE IFGTILLCIV ATTFIVRRLF HPQPHRQRKE 550
SETQCQTESK YDSVSADVSD NSWNDMKYSG YVSRYLTDFE PIQCMGRGGF 600
GVVFEAKNKV DDCNYAIKRI RLPNRELARE KVMREVKALA KLEHPGIVRY 650
FNAWLETPPE KWQEEMDEIW LKDESTDWPL SSPSPMDAPS VKIRRMDPFS 700
TKEQIEVIAP SPERSRSFSV GISCGQTSSS ESQFSPLEFS GTDCGDNSDS 750
ADAAYNLQDS CLTDCEDVED GTVDGNDEGH SFELCPSEAS PYTRSREGTS 800
SSIVFEDSGC GNASSKEEPR GNRLHDGNHY VNKLTDLKCS SSRSSSEATT 850
LSTSPTRPTT LSLDFTKNTV GQLQPSSPKV YLYIQMQLCR KENLKDWMNR 900
RCSLEDREHG VCLHIFLQIA EAVEFLHSKG LMHRDLKPSN IFFTMDDVVK 950
VGDFGLVTAM DQDEEEQTVL TPMPAYATHT GQVGTKLYMS PEQIHGNNYS 1000
HKVDIFSLGL ILFELLYPFS TQMERVRILT DVRNLKFPLL FTQKYPQEHM 1050
MVQDMLSPSP TERPEATDII ENAIFENLEF PGKTVLRQRS RSMSSSGTKH 1100
SRQPSCSYSP LPGN 1114
Length:1,114
Mass (Da):124,682
Last modified:May 1, 1999 - v1
Checksum:i65A47D6C0DD2E046
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti143 – 15210VFGNKMIIPS → GTHKTSSKEC in BAB26908. 1 Publication
Sequence conflicti826 – 8261Missing in BAB22655. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF076681 mRNA. Translation: AAD03337.1.
AK010397 mRNA. Translation: BAB26908.1.
AK003226 mRNA. Translation: BAB22655.1.
CCDSiCCDS20223.1.
PIRiT14351.
UniGeneiMm.247167.

Genome annotation databases

EnsembliENSMUST00000162950; ENSMUSP00000123759; ENSMUSG00000031668.
UCSCiuc009cgc.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF076681 mRNA. Translation: AAD03337.1 .
AK010397 mRNA. Translation: BAB26908.1 .
AK003226 mRNA. Translation: BAB22655.1 .
CCDSi CCDS20223.1.
PIRi T14351.
UniGenei Mm.247167.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
3QD2 X-ray 2.81 B 583-1078 [» ]
ProteinModelPortali Q9Z2B5.
SMRi Q9Z2B5. Positions 99-213, 583-668, 826-1103.
ModBasei Search...

Protein-protein interaction databases

IntActi Q9Z2B5. 3 interactions.
STRINGi 10090.ENSMUSP00000034093.

PTM databases

PhosphoSitei Q9Z2B5.

Proteomic databases

PaxDbi Q9Z2B5.
PRIDEi Q9Z2B5.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000162950 ; ENSMUSP00000123759 ; ENSMUSG00000031668 .
UCSCi uc009cgc.1. mouse.

Organism-specific databases

MGIi MGI:1341830. Eif2ak3.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00530000062984.
HOGENOMi HOG000112308.
HOVERGENi HBG051431.
InParanoidi Q9Z2B5.
PhylomeDBi Q9Z2B5.

Miscellaneous databases

PROi Q9Z2B5.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q9Z2B5.
Bgeei Q9Z2B5.
Genevestigatori Q9Z2B5.

Family and domain databases

Gene3Di 2.140.10.10. 1 hit.
InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR027295. Quinonprotein_ADH-like_fam.
IPR011047. Quinonprotein_ADH-like_supfam.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 2 hits.
[Graphical view ]
SUPFAMi SSF50998. SSF50998. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEi PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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.

Entry informationi

Entry nameiE2AK3_MOUSE
AccessioniPrimary (citable) accession number: Q9Z2B5
Secondary accession number(s): Q9CTK8, Q9CWT5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 1999
Last modified: July 9, 2014
This is version 135 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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