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Q9NZJ5 · E2AK3_HUMAN

  • Protein
    Eukaryotic translation initiation factor 2-alpha kinase 3
  • Gene
    EIF2AK3
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR) (PubMed:10026192, PubMed:10677345, PubMed:11907036, PubMed:12086964, PubMed:25925385, PubMed:31023583).
Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation (PubMed:10677345, PubMed:27917829, PubMed:31023583).
EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:10026192, PubMed:10677345, PubMed:31023583, PubMed:33384352).
The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes (PubMed:31023583).
In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites (PubMed:39116259).
In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2 (By similarity).
Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity).
Involved in control of mitochondrial morphology and function (By similarity).

Catalytic activity

Activity regulation

Inhibited by HSPA5/BIP in absence of stress (PubMed:11907036).
Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in trans-autophosphorylation and kinase activity induction (PubMed:11907036).
Inactivated following phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) (By similarity).
Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress (PubMed:39116259).

Features

Showing features for binding site, active site.

Type
IDPosition(s)Description
Binding site599-607ATP (UniProtKB | ChEBI)
Binding site622ATP (UniProtKB | ChEBI)
Active site937Proton acceptor

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentendoplasmic reticulum
Cellular Componentendoplasmic reticulum membrane
Cellular Componentmembrane
Cellular Componentnucleus
Cellular Componentperinuclear region of cytoplasm
Molecular FunctionATP binding
Molecular Functionenzyme binding
Molecular Functioneukaryotic translation initiation factor 2alpha kinase activity
Molecular Functionhistone H2AS1 kinase activity
Molecular FunctionHsp90 protein binding
Molecular Functionidentical protein binding
Molecular Functionprotein kinase activity
Molecular Functionprotein phosphatase binding
Molecular Functionprotein serine kinase activity
Molecular Functionprotein serine/threonine kinase activity
Biological Processactivation of cysteine-type endopeptidase activity involved in apoptotic process
Biological Processangiogenesis
Biological Processbone mineralization
Biological Processcalcium-mediated signaling
Biological Processcellular response to amino acid starvation
Biological Processcellular response to cold
Biological Processcellular response to glucose starvation
Biological Processchondrocyte development
Biological ProcesseiF2alpha phosphorylation in response to endoplasmic reticulum stress
Biological Processendocrine pancreas development
Biological Processendoplasmic reticulum organization
Biological Processendoplasmic reticulum unfolded protein response
Biological ProcessER overload response
Biological Processinsulin-like growth factor receptor signaling pathway
Biological Processnegative regulation of myelination
Biological Processnegative regulation of translation
Biological Processnegative regulation of translation in response to stress
Biological Processnegative regulation of translational initiation
Biological Processnegative regulation of translational initiation in response to stress
Biological Processossification
Biological Processpeptidyl-serine phosphorylation
Biological ProcessPERK-mediated unfolded protein response
Biological Processpositive regulation of gene expression
Biological Processpositive regulation of protein localization to nucleus
Biological Processpositive regulation of transcription by RNA polymerase I
Biological Processpositive regulation of vascular endothelial growth factor production
Biological Processprotein autophosphorylation
Biological Processprotein phosphorylation
Biological Processregulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation
Biological Processregulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
Biological Processregulation of translational initiation by eIF2 alpha phosphorylation
Biological Processresponse to endoplasmic reticulum stress
Biological Processresponse to manganese-induced endoplasmic reticulum stress
Biological Processskeletal system development

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

  • Recommended name
    Eukaryotic translation initiation factor 2-alpha kinase 3
  • EC number
  • Alternative names
    • PRKR-like endoplasmic reticulum kinase
    • Pancreatic eIF2-alpha kinase
      (HsPEK
      )
    • Protein tyrosine kinase EIF2AK3
      (EC:2.7.10.2
      ) . EC:2.7.10.2 (UniProtKB | ENZYME | Rhea)

Gene names

    • Name
      EIF2AK3
    • Synonyms
      PEK
      , PERK

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    Q9NZJ5
  • Secondary accessions
    • A0AVH1
    • A0AVH2
    • B2RCU9
    • O95846
    • Q53QY0
    • Q53SB1

Proteomes

Organism-specific databases

Subcellular Location

Endoplasmic reticulum membrane
; Single-pass type I membrane protein
Note: Localizes to the Localizes to endoplasmic reticulum membrane (By similarity).
Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (PubMed:39116259).

Features

Showing features for topological domain, transmembrane.

Type
IDPosition(s)Description
Topological domain30-514Lumenal
Transmembrane515-535Helical
Topological domain536-1116Cytoplasmic

Keywords

Disease & Variants

Involvement in disease

Wolcott-Rallison syndrome (WRS)

  • Note
    • The disease is caused by variants affecting the gene represented in this entry
  • Description
    A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, intellectual disability and cardiovascular abnormalities.
  • See also
    MIM:226980
Natural variants in WRS
Variant IDPosition(s)ChangeDescription
VAR_08992769-1116missingin WRS
VAR_089928332-1116missingin WRS
VAR_089929334-1116missingin WRS
VAR_011408588R>Qin WRS; dbSNP:rs121908569
VAR_089930658W>Sin WRS; uncertain significance
VAR_089931878S>Pin WRS; decreased ability to phosphorylate EIF2S1/eIF-2-alpha
VAR_089932903-1116missingin WRS; uncertain significance
VAR_089933940P>Sin WRS; uncertain significance
VAR_089934994E>Qin WRS; uncertain significance
VAR_0899351065-1116missingin WRS

Features

Showing features for natural variant, mutagenesis.

Type
IDPosition(s)Description
Natural variantVAR_08992769-1116in WRS
Natural variantVAR_011409136in dbSNP:rs867529
Mutagenesis164Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha.
Natural variantVAR_011410166in dbSNP:rs13045
Natural variantVAR_089928332-1116in WRS
Natural variantVAR_089929334-1116in WRS
Mutagenesis388Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha.
Mutagenesis395Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha.
Mutagenesis397Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha.
Natural variantVAR_040477566in dbSNP:rs55791823
Natural variantVAR_011408588in WRS; dbSNP:rs121908569
Natural variantVAR_089930658in WRS; uncertain significance
Natural variantVAR_011411704in dbSNP:rs1805165
Natural variantVAR_040478716in dbSNP:rs55861585
Natural variantVAR_089931878in WRS; decreased ability to phosphorylate EIF2S1/eIF-2-alpha
Natural variantVAR_089932903-1116in WRS; uncertain significance
Natural variantVAR_089933940in WRS; uncertain significance
Natural variantVAR_089934994in WRS; uncertain significance
Natural variantVAR_0899351065-1116in WRS

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 1,218 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Keywords

Organism-specific databases

Miscellaneous

Chemistry

Genetic variation databases

PTM/Processing

Features

Showing features for signal, chain, glycosylation, modified residue (large scale data), modified residue.

Type
IDPosition(s)Source
Description
Signal1-29UniProt
ChainPRO_000002432230-1116UniProtEukaryotic translation initiation factor 2-alpha kinase 3
Glycosylation258UniProtN-linked (GlcNAc...) asparagine
Modified residue (large scale data)555PRIDEPhosphoserine
Modified residue (large scale data)561PRIDEPhosphothreonine
Modified residue (large scale data)567PRIDEPhosphoserine
Modified residue619UniProtPhosphotyrosine; by autocatalysis
Modified residue (large scale data)685PRIDEPhosphoserine
Modified residue (large scale data)686PRIDEPhosphoserine
Modified residue (large scale data)688PRIDEPhosphoserine
Modified residue715UniProtPhosphoserine
Modified residue (large scale data)715PRIDEPhosphoserine
Modified residue (large scale data)719PRIDEPhosphoserine
Modified residue802UniProtPhosphothreonine
Modified residue (large scale data)844PRIDEPhosphoserine
Modified residue (large scale data)845PRIDEPhosphoserine
Modified residue982UniProtPhosphothreonine
Modified residue1094UniProtPhosphoserine
Modified residue (large scale data)1094PRIDEPhosphoserine
Modified residue (large scale data)1096PRIDEPhosphoserine
Modified residue (large scale data)1106PRIDEPhosphoserine
Modified residue (large scale data)1109PRIDEPhosphoserine
Modified residue (large scale data)1111PRIDEPhosphoserine

Post-translational modification

Oligomerization of the N-terminal ER luminal domain by ER stress promotes EIF2AK3/PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity).
Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity (PubMed:22169477).
Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity (PubMed:22169477).
Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (By similarity).
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Ubiquitous. A high level expression is seen in secretory tissues.

Induction

By endoplasmic reticulum stress.

Gene expression databases

Organism-specific databases

Interaction

Subunit

Forms dimers with HSPA5/BIP in resting cells (PubMed:11907036).
Homotetramerizes in response to endoplasmic reticulum (ER) stress, leading to its activation (PubMed:25925385).
Interacts with HSP90B1/GRP94 (PubMed:11907036).
Interacts with DNAJC3; inhibiting EIF2AK3/PERK activity (By similarity).
Interacts with ATAD3A; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha (PubMed:39116259).
Interacts with MFN2 (By similarity).
Interacts with TMEM33 (PubMed:26268696).
Interacts with PDIA6 (PubMed:24508390).
Interacts with LACC1 (PubMed:31875558).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntAct
BINARY Q9NZJ5EIF2AK3 Q9NZJ52EBI-766076, EBI-766076
BINARY Q9NZJ5HSPA5 P110214EBI-766076, EBI-354921

Protein-protein interaction databases

Chemistry

Miscellaneous

Family & Domains

Features

Showing features for region, compositional bias, domain.

Type
IDPosition(s)Description
Region77-101Disordered
Compositional bias87-101Basic and acidic residues
Region550-571Disordered
Domain593-1077Protein kinase
Region647-888Insert loop
Region841-863Disordered
Region1090-1116Disordered

Domain

The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.
The insert loop specifically recongnizes and binds EIF2S1/eIF-2-alpha.

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    1,116
  • Mass (Da)
    125,216
  • Last updated
    2010-05-18 v3
  • MD5 Checksum
    A1CF86ECF6D850F68C026C5587994C17
MERAISPGLLVRALLLLLLLLGLAARTVAAGRARGLPAPTAEAAFGLGAAAAPTSATRVPAAGAVAAAEVTVEDAEALPAAAGEQEPRGPEPDDETELRPRGRSLVIISTLDGRIAALDPENHGKKQWDLDVGSGSLVSSSLSKPEVFGNKMIIPSLDGALFQWDQDRESMETVPFTVESLLESSYKFGDDVVLVGGKSLTTYGLSAYSGKVRYICSALGCRQWDSDEMEQEEDILLLQRTQKTVRAVGPRSGNEKWNFSVGHFELRYIPDMETRAGFIESTFKPNENTEESKIISDVEEQEAAIMDIVIKVSVADWKVMAFSKKGGHLEWEYQFCTPIASAWLLKDGKVIPISLFDDTSYTSNDDVLEDEEDIVEAARGATENSVYLGMYRGQLYLQSSVRISEKFPSSPKALESVTNENAIIPLPTIKWKPLIHSPSRTPVLVGSDEFDKCLSNDKFSHEEYSNGALSILQYPYDNGYYLPYYKRERNKRSTQITVRFLDNPHYNKNIRKKDPVLLLHWWKEIVATILFCIIATTFIVRRLFHPHPHRQRKESETQCQTENKYDSVSGEANDSSWNDIKNSGYISRYLTDFEPIQCLGRGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLEAPPEKWQEKMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFATKEHIEIIAPSPQRSRSFSVGISCDQTSSSESQFSPLEFSGMDHEDISESVDAAYNLQDSCLTDCDVEDGTMDGNDEGHSFELCPSEASPYVRSRERTSSSIVFEDSGCDNASSKEEPKTNRLHIGNHCANKLTAFKPTSSKSSSEATLSISPPRPTTLSLDLTKNTTEKLQPSSPKVYLYIQMQLCRKENLKDWMNGRCTIEERERSVCLHIFLQIAEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVTAMDQDEEEQTVLTPMPAYARHTGQVGTKLYMSPEQIHGNSYSHKVDIFSLGLILFELLYPFSTQMERVRTLTDVRNLKFPPLFTQKYPCEYVMVQDMLSPSPMERPEAINIIENAVFEDLDFPGKTVLRQRSRSLSSSGTKHSRQSNNSHSPLPSN

Computationally mapped potential isoform sequences

There are 8 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
A0A804HI66A0A804HI66_HUMANEIF2AK317
A0A494BZR8A0A494BZR8_HUMANEIF2AK3225
A0A804HIT4A0A804HIT4_HUMANEIF2AK3965
A0A804HJ50A0A804HJ50_HUMANEIF2AK3859
A0A804HLC2A0A804HLC2_HUMANEIF2AK3177
A0A804HJV6A0A804HJV6_HUMANEIF2AK379
A0A804HL08A0A804HL08_HUMANEIF2AK3139
A0A494C186A0A494C186_HUMANEIF2AK363

Features

Showing features for sequence conflict, compositional bias.

Type
IDPosition(s)Description
Sequence conflict14in Ref. 1; AAD19961, 2; AAF61199, 3; AAF91480, 4; BAG37696 and 6; AAI26357
Compositional bias87-101Basic and acidic residues
Sequence conflict490in Ref. 2; AAF61199

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF110146
EMBL· GenBank· DDBJ
AAD19961.1
EMBL· GenBank· DDBJ
mRNA
AF193339
EMBL· GenBank· DDBJ
AAF61199.1
EMBL· GenBank· DDBJ
mRNA
AF284615
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284604
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284605
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284606
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284607
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284608
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284609
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284610
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284611
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284612
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284613
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AF284614
EMBL· GenBank· DDBJ
AAF91480.1
EMBL· GenBank· DDBJ
Genomic DNA
AK315287
EMBL· GenBank· DDBJ
BAG37696.1
EMBL· GenBank· DDBJ
mRNA
AC062029
EMBL· GenBank· DDBJ
AAY14777.1
EMBL· GenBank· DDBJ
Genomic DNA
AC104134
EMBL· GenBank· DDBJ
AAY24331.1
EMBL· GenBank· DDBJ
Genomic DNA
BC126354
EMBL· GenBank· DDBJ
AAI26355.1
EMBL· GenBank· DDBJ
mRNA
BC126356
EMBL· GenBank· DDBJ
AAI26357.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
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